Aminopyrimidine kinase inhibitors

ABSTRACT

Disclosed are compounds, pharmaceutical compositions containing those compounds, and uses of the compounds and compositions as modulators of casein kinase 1 (e.g., CK1γ), casein kinase 2 (CK2), Pim 1, Pim2, Pim3, the TGFβ pathway, the Wnt pathway, the JAK/STAT pathway, and/or the mTOR pathway. Uses are also disclosed for the treatment or prevention of a range of therapeutic indications due at least in part to aberrant physiological activity of casein kinase 1 (e.g., CK1γ), casein kinase 2 (CK2), Pim 1, Pim2, Pim3, the TGFβ pathway, the Wnt pathway, the JAK/STAT pathway, and/or the mTOR pathway.

RELATED APPLICATIONS

This application claims the benefit of priority to U.S. Provisional Patent Application Ser. No. 61/289,685, filed Dec. 23, 2009; and U.S. Provisional Patent Application Ser. No. 61/324,481, filed Apr. 15, 2010.

BACKGROUND OF THE INVENTION

Casein kinase 1 (CK1) is a family of evolutionarily conserved serine/threonine kinases including seven known members in vertebrates (CK1α, -β, -γ1, -γ2, -γ3, -δ and -ε). The CK1s contain a typical kinase domain followed by a C-terminal tail region, which has been implicated in the regulation of CK1 localization, substrate selectivity and kinase activity. Myriad proteins have been found to be phosphorylated by CK1s, which are involved in a wide range of cellular functions including vesicular trafficking, DNA damage repair, cell cycle progression, cytokinesis and circadian rhythms (reviewed by Gross and Anderson (1998); Vielhaber and Virshup (2001); Knippschild et al. (2005)). Moreover, CK1 family members (-α, -δ/ε and -γ) modulate the activities of major signaling pathways (for example, Wnt and Shh) through several mechanisms (Peters et al., 1999; Liu et al., 2002; Price and Kalderon, 2002; Davidson et al., 2005; Zeng et al., 2005 and reviewed by Price (2006)).

In mammals seven CK1 isoforms, namely CK1α, β, γ₁₋₃, δ and ε, and several splice variants have been described. They all contain a highly conserved kinase domain, a short N-terminal domain of 6 to 76 amino acids and a highly variable C-terminal domain of 24 to more than 200 amino acids. The constitutive phosphotransferase activity of CK1 isoforms is tightly controlled by several mechanisms. For example, the closely related isoforms CK1δ and ε, which share a 98% identity at the amino acid level in their catalytic domain, are regulated by autophosphorylation, dephosphorylation and proteolytic cleavage. Members of the CK1 family are found in the nucleus, the cytoplasm and in the plasma membrane. By phosphorylating many different substrates bearing either a canonical or non-canonical consensus sequence they modulate the activity of key regulator proteins involved in many cellular processes such as cell differentiation, cell proliferation, apoptosis, circadian rhythm, chromosome segregation, and vesicle transport.

The Pim kinase family contains three isoforms, Pim-1, Pim-2 and Pim-3, and has recently emerged as targets of interest in oncology and immune regulation. Ongoing studies have identified a role for these proteins in cell survival and proliferation, both functionally and mechanistically, and overexpression has been observed in a number of human cancers and inflammatory states.

Pim kinases suppress apoptosis and regulate cell-cycle progression. Elevated levels of Pim kinases have been reported in solid tumors such as prostate cancer and pancreatic cancer. Pim-1 was initially discovered in murine leukemia and several independent studies have shown this kinase to be upregulated in human prostate cancer. Pim-1, 2 and 3 make up a distinct and highly homologous family of serine/threonine kinases belonging to the calmodulin-dependent protein kinase-related (CAMK) family. In addition to the three gene-encoded proteins, translational variants have also been reported for Pim-1 and 2 resulting from utilization of alternative start codons. The name Pim refers to the original identification of the pim-1 gene as a frequent proviral insertion site in Moloney murine leukemia virus-induced T-cell lymphomas, and the gene encoding Pim-2 was subsequently found to have similar susceptibility. Pim-3, originally designated kinase induced by depolarization (KID)-1, was later renamed due to high sequence similarity to Pim-1 (71% identity at the amino acid level). Considering all three isoforms, Pim proteins are widely expressed with high levels in hematopoietic tissue and are aberrantly expressed in a variety of human malignancies. Pim kinases positively regulate cell survival and proliferation, affording therapeutic opportunities in oncology. The Pim protein kinases are frequently overexpressed in prostate cancer and certain forms of leukemia and lymphoma.

A role for Pim kinases in immune regulation has also been observed. Pim-2 has been reported to have enhanced levels of expression in a variety of inflammatory states and may function as a positive regulator of interleukin-6 (IL-6), whereby overexpression of the kinase augments stimulus-induced IL-6 levels. Pim-1 and 2 have also been implicated in cytokine-induced T-cell growth and survival. Comparing the sensitivity of stimulated T cells from Pim-1−/−Pim-2−/− mice to wild-type mice following treatment with the immunosuppressant rapamycin, it was found that T-cell activation was significantly impaired by Pim-1/Pim-2 deficiency, suggesting that Pim kinases promote lymphocyte growth and survival through a PI3K/AKT (PKB, protein kinase B)/mammalian target of rapamycin (mTOR)-independent pathway. Other parallel but independent functions and overlapping substrate specificity for proteins in these pathways have been reported as well, including the positive regulation of transcription of nuclear factor kappa-B (NF-κB)-responsive genes, which have implications in both inflammation and oncology. Therefore, Pim kinases are attractive targets for both therapeutic areas. Further, Pim kinases have been reported to play a role in the protection of the ATP-binding cassette (ABC) transporter P-glycoprotein (Pgp; ABCB1) from proteolytic and proteasomal degradation. Pgp is known to mediate drug efflux and as such, inhibitors of Pim kinases may provide a novel approach to abrogating drug resistance.

SUMMARY OF THE INVENTION

An aspect of the present invention relates to compounds that inhibit casein kinase 1 and/or casein kinase 2 and/or a PIM kinase. For example, an embodiment relates to a compound of formula 1:

or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence: W and X are independently oxygen or sulfur; Z¹, Z² and Z³ are independently C—R²⁰ or N, provided that at least one of Z¹ and Z² is N; R¹ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —COR⁶, —C(O)OR⁶, —SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —[C(R⁴)₂]_(p)—R⁵; R² and R³ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶, —SO₂(R⁶), —C(O)_(N)(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), —P(O)(OR⁶)(OR⁷); or R² and R³ are joined together to form an optionally substituted heterocyclic ring; R⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl; R⁵ is selected from the group consisting of aryl, heteroaryl, heterocyclyl, —N(R⁸)(R⁹), —N(R⁸)COR⁹, —N(R⁸)C(O)OR⁹, —N(R⁸)SO₂(R⁹), —CON(R⁸)(R⁹), —OC(O)N(R⁸)—(R⁹), —SO₂N(R⁸)(R⁹), —OC(O)OR⁸, —COOR⁸, —C(O)N(OH)(R⁸), —OS(O)₂OR⁸, —S(O)₂OR⁸, —S(O)₂R⁸, —OR⁸, —COR⁸, —OP(O)(OR⁸)(OR⁸), —P(O)(OR⁸)(OR⁸) and —N(R⁸)P(O)(OR⁹)(OR⁹); R⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; R⁷ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R⁶ and R⁷ are joined together to form a heterocyclic ring; R⁸ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; R⁹ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R⁸ and R⁹ are joined together to form a heterocyclic ring; R²⁰ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, halo, haloalkyl, trifluoromethyl, fluoroalkyl, perfluoroalkyl, thio, cyano, hydroxy, methoxy, alkoxy, phenoxy, aryloxy, heteroaryloxy, carboxyl, alkoxycarbonyl, acyl, nitro, amino, alkylamino, arylamino, heteroarylamino, amido, acylamino, sulfate, sulfonate, sulfonyl, sulfoxido, sulfonamido, sulfamoyl, —[C(R⁴)₂]_(p)—R⁵, NR¹⁴R¹⁵, OR¹⁶, O—[C(R⁴)₂]_(p)—R⁵, NR¹⁴—[C(R⁴)₂]_(p)—R⁵ and SR¹⁶; R¹⁴ and R¹⁵ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶, —SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —P(O)(OR⁶)(OR⁷); or R¹⁴ and R¹⁵ are joined together to form an optionally substituted heterocyclic ring; R¹⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, and —C(O)N(R⁶)(R⁷); and p is 1, 2, 3, 4, 5, or 6;

wherein any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted.

An embodiment relates to a compound of formula 2:

or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence: R¹ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —COR⁶, —C(O)OR⁶, —SO₂(R⁶), —C(O)_(N)(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —[C(R⁴)₂]_(p)—R⁵; R² and R³ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶, —SOAR), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷)—P(O)(OR⁶)(OR⁷); or R² and R³ are joined together to form an optionally substituted heterocyclic ring; R⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl; R⁵ is selected from the group consisting of aryl, heteroaryl, heterocyclyl, —N(R⁸)(R⁹), —N(R⁸)COR⁹, —N(R⁸)C(O)OR⁹, —N(R⁸)SO₂(R⁹), —CON(R⁸)(R⁹), —OC(O)N(R⁸)—(R⁹), —SO₂N(R⁸)(R⁹), —OC(O)OR⁸, —COOR⁸, —C(O)N(OH)(R⁸), —OS(O)₂OR⁸, —S(O)₂OR⁸, —S(O)₂R⁸, —OR⁸, —COR⁸, —OP(O)(OR⁸)(OR⁹), —P(O)(OR⁸)(OR⁹) and —N(R⁸)P(O)(OR⁹)(OR⁹); R⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; R⁷ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl, or R⁶ and R⁷ are joined together to form a heterocyclic ring; R⁸ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; R⁹ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R⁸ and R⁹ are joined together to form a heterocyclic ring; R²⁰ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, halo, haloalkyl, trifluoromethyl, fluoroalkyl, perfluoroalkyl, thio, cyano, hydroxyl, methoxy, alkoxy, phenoxy, aryloxy, heteroaryloxy, carboxyl, alkoxycarbonyl, acyl, nitro, amino, alkylamino, arylamino, heteroarylamino, amido, acylamino, sulfate, sulfonate, sulfonyl, sulfoxido, sulfonamido, sulfamoyl, —[C(R⁴)₂]_(p)—R⁵; NR¹⁴R¹⁵, OR¹⁶, and SR¹⁶; R¹⁴ and R¹⁵ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶, —SO₂(R⁶), —C(O)_(N)(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —P(O)(OR⁶)(OR⁷); or R¹⁴ and R¹⁵ are joined together to form an optionally substituted heterocyclic ring; R¹⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, and —C(O)N(R⁶)(R⁷); and p is 1, 2, 3, 4, 5, or 6;

wherein any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted.

An aspect of the invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

An aspect of the invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of CK1, CK1γ1, CK1γ2, or CK1γ3. In one embodiment the compound has an IC₅₀ of less than 5000 nM for CK1, CK1γ1, CK1γ2, or CK1γ3. In one embodiment the compound has an IC₅₀ of less than 1000 nM for CK1, CK1γ1, CK1γ2, or CK1γ3. In one embodiment the compound has an IC₅₀ of less than 500 nM for CK1, CK1γ1, CK1γ2, or CK1γ3.

An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of CK2. In one embodiment the compound has an IC₅₀ of less than 5000 nM for CK2. In one embodiment the compound has an IC₅₀ of less than 1000 nM for CK2. In one embodiment the compound has an IC₅₀ of less than 500 nM for CK2.

An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of PIM1, PIM2, or PIM3. In one embodiment the compound has an IC₅₀ of less than 5000 nM for PIM1, PIM2, or PIM3. In one embodiment the compound has an IC₅₀ of less than 1000 nM for PIM1, PIM2, or PIM3. In one embodiment the compound has an IC₅₀ of less than 500 nM for PIM1, PIM2, or PIM3.

An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of the Wnt pathway.

An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of the TGFβ pathway.

An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of the JAK/STAT pathway.

An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of the mTOR pathway.

An embodiment relates to any one of the aforementioned compounds, wherein the compound is a modulator of Pgp degradation, drug efflux, or drug resistance.

An embodiment relates to a pharmaceutical composition comprising any one or combination of the aforementioned compounds, and a pharmaceutically acceptable carrier.

Another embodiment relates to a method of inhibiting CK1 activity, comprising contacting CK1, CK1γ1, CK1γ2, or CK1γ3 with any one of the aforementioned compounds or pharmaceutical compositions.

Another embodiment relates to a method of inhibiting CK2 activity, comprising contacting CK2 with any one of the aforementioned compounds or pharmaceutical compositions.

Another embodiment relates to a method of treating or preventing a condition associated with aberrant CK1, CK1γ1, CK1γ2, or CK1γ3 activity, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.

Another embodiment relates to a method of treating or preventing a condition associated with aberrant CK2 activity, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.

Another embodiment relates to a method of treating cancer, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions. In one embodiment the cancer is a cancer of a system selected from the group consisting of the hematopoietic system, immune system, endocrine system, pulmonary system, gastrointestinal system, musculoskeletal system, reproductive system, central nervous system, and urologic system. In one embodiment the cancer is located in the mammal's myeloid tissues, lymphoid tissues, pancreatic tissues, thyroid tissues, lung tissues, colon tissues, rectal tissues, anal tissues, liver tissues, skin, bone, ovarian tissues, uterine tissues, cervical tissues, breast, prostate, testicular tissues, brain, brainstem, meningeal tissues, kidney or bladder. In one embodiment the cancer is selected from the group consisting of breast cancer, colon cancer, multiple myeloma, prostate cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, hematologic malignancy, renal cell carcinoma, renal cancer, malignant melanoma, pancreatic cancer, lung cancer, colorectal carcinoma, brain cancer, head and neck cancer, bladder cancer, thyroid cancer, ovarian cancer, cervical cancer, and myelodysplastic syndrome.

Another embodiment relates to a method of treating leukemia or other hematologic malignancies, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.

Another embodiment relates to a method of treating Alzheimer's disease, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.

Another embodiment relates to a method of treating a Wnt-dependent disease, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.

Another embodiment relates to a method of treating a TGFβ-dependent disease, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.

Another embodiment relates to a method of treating a JAK/STAT-dependent disease, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.

Another embodiment relates to a method of treating an mTOR-dependent disease, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.

Another embodiment relates to a method of treating or preventing inflammation, inflammatory diseases (e.g., osteoarthritis and rheumatoid arthritis), neurological conditions (e.g., Alzheimer's disease) and neurodegeneration, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.

Another embodiment relates to a method of treating or preventing bone-related diseases and conditions, including osteoporosis and bone formation, or facilitating bone restoration, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.

Another embodiment relates to a method of treating or preventing hypoglycemia, metabolic syndrome and diabetes, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.

Another embodiment relates to a method of influencing apoptosis (e.g., increasing the rate of apoptosis in cancerous cells), comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.

Another embodiment relates to a method of treating or preventing aberrant embryonic development, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.

Another embodiment relates to a method of inhibiting PIM activity, comprising contacting PIM1, PIM2 or PIM3 with any one of the aforementioned compounds or pharmaceutical compositions.

Another embodiment relates to a method for treating or preventing a condition associated with aberrant PIM activity, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.

Another embodiment relates to a method of modulating Pgp degradation and/or drug efflux activity, comprising contacting a cell with any one of the aforementioned compounds or pharmaceutical compositions.

Another embodiment relates to a method for treating a malignancy based upon modulation of Pgp, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions.

Another embodiment relates to a method for treating a malignancy based upon modulation of Pgp, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions, in conjunction with another drug, compound, or material, to abrogate resistance to the drug, compound, or material.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts the relative activity of CK1γ1(h) as a function of the concentration of compound 4981.

FIG. 2 depicts the relative activity of CK1γ2(h) as a function of the concentration of compound 4981.

FIG. 3 depicts the relative activity of CK1γ3(h) as a function of the concentration of compound 4981.

FIG. 4 depicts the relative activity of CK1δ(h) as a function of the concentration of compound 4981.

FIG. 5 depicts the relative activity of CK1(y) as a function of the concentration of compound 4981.

FIG. 6 depicts the relative activity of CK1γ1(h) as a function of the concentration of compound 4993.

FIG. 7 depicts the relative activity of CK1γ2(h) as a function of the concentration of compound 4993.

FIG. 8 depicts the relative activity of CK1γ3(h) as a function of the concentration of compound 4993.

FIG. 9 depicts the relative activity of CK1δ(h) as a function of the concentration of compound 4993.

FIG. 10 depicts the relative activity of CK1(y) as a function of the concentration of compound 4993.

FIG. 11 depicts the relative activity of CK1γ1(h) as a function of the concentration of compound 4991.

FIG. 12 depicts the relative activity of CK1γ2(h) as a function of the concentration of compound 4991.

FIG. 13 depicts the relative activity of CK1γ3(h) as a function of the concentration of compound 4991.

FIG. 14 depicts the relative activity of CK1δ(h) as a function of the concentration of compound 4991.

FIG. 15 depicts the relative activity of CK1(y) as a function of the concentration of compound 4991.

FIG. 16 depicts the relative activity of CK1γ1(h) as a function of the concentration of compound 4999.

FIG. 17 depicts the relative activity of CK1γ2(h) as a function of the concentration of compound 4999.

FIG. 18 depicts the relative activity of CK1γ3(h) as a function of the concentration of compound 4999.

FIG. 19 depicts the relative activity of CK1δ(h) as a function of the concentration of compound 4999.

FIG. 20 depicts the relative activity of CK1(y) as a function of the concentration of compound 4999.

FIG. 21 depicts the relative activity of CK1γ1(h) as a function of the concentration of compound 4985.

FIG. 22 depicts the relative activity of CK1γ2(h) as a function of the concentration of compound 4985.

FIG. 23 depicts the relative activity of CK1γ3(h) as a function of the concentration of compound 4985.

FIG. 24 depicts the relative activity of CK1δ(h) as a function of the concentration of compound 4985.

FIG. 25 depicts the relative activity of CK1(y) as a function of the concentration of compound 4985.

FIG. 26 depicts the relative activity of CK1γ1(h) as a function of the concentration of compound 4992.

FIG. 27 depicts the relative activity of CK1γ2(h) as a function of the concentration of compound 4992.

FIG. 28 depicts the relative activity of CK1γ3(h) as a function of the concentration of compound 4992.

FIG. 29 depicts the relative activity of CK1δ(h) as a function of the concentration of compound 4992.

FIG. 30 depicts the relative activity of CK1(y) as a function of the concentration of compound 4992.

FIG. 31 depicts the relative activity of CK1γ1(h) as a function of the concentration of compound 4996.

FIG. 32 depicts the relative activity of CK1γ2(h) as a function of the concentration of compound 4996.

FIG. 33 depicts the relative activity of CK1γ3(h) as a function of the concentration of compound 4996.

FIG. 34 depicts the relative activity of CK1δ(h) as a function of the concentration of compound 4996.

FIG. 35 depicts the relative activity of CK1(y) as a function of the concentration of compound 4996.

FIG. 36 depicts the relative activity of CK1γ1(h) as a function of the concentration of compound 5000.

FIG. 37 depicts the relative activity of CK1γ2(h) as a function of the concentration of compound 5000.

FIG. 38 depicts the relative activity of CK1γ3(h) as a function of the concentration of compound 5000.

FIG. 39 depicts the relative activity of CK1δ(h) as a function of the concentration of compound 5000.

FIG. 40 depicts the relative activity of CK1(y) as a function of the concentration of compound 5000.

FIG. 41 depicts the dose-response curve and EC₅₀ of gemcitabine against PC-3 cells, which data served as an experimental control.

FIG. 42 depicts the dose-response curve and EC₅₀ of gemcitabine against OVCAR-3 cells, which data served as an experimental control.

FIG. 43 depicts the dose-response curve and EC₅₀ of gemcitabine against LNCaP cells, which data served as an experimental control.

FIG. 44 depicts the dose-response curve and EC₅₀ of gemcitabine against Jurkat cells, which data served as an experimental control.

FIG. 45 depicts the dose-response curve and EC₅₀ of gemcitabine against MDA-MB-468 cells, which data served as an experimental control.

FIG. 46 depicts the dose-response curve and IC₅₀ of gemcitabine against HCT116 cells, which data served as an experimental control.

FIG. 47 depicts the dose-response curve and IC₅₀ of gemcitabine against A549 cells, which data served as an experimental control.

FIG. 48 depicts the dose-response curve and IC₅₀ of gemcitabine against DU145 cells, which data served as an experimental control.

FIG. 49 depicts the dose-response curve and IC₅₀ of sorafenib against HC1954 cells, which data served as an experimental control.

FIG. 50 depicts the dose-response curve and EC₅₀ of sorafenib against Caco-2 cells, which data served as an experimental control.

FIG. 51 depicts the dose response curve and IC₅₀ of compound 4991 against OVCAR-3 cells compared to cisplatin.

FIG. 52 depicts the dose response curve and IC₅₀ of compound 4991 against OVCAR-8 cells compared to cisplatin.

FIG. 53 depicts the dose response curve and IC₅₀ of compound 4991 against SK-OV-3 cells compared to cisplatin.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The definitions of terms used herein are meant to incorporate the present state-of-the-art definitions recognized for each term in the chemical and pharmaceutical fields. Where appropriate, illustration is provided. The definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.

Where stereochemistry is not specifically indicated, all stereoisomers of the inventive compounds are included within the scope of the invention, as pure compounds as well as mixtures thereof. Unless otherwise indicated, individual enantiomers, diastereomers, geometrical isomers, and combinations and mixtures thereof are all encompassed by the present invention. Polymorphic crystalline forms and solvates are also encompassed within the scope of this invention.

As used herein, the term “isolated” in connection with a compound of the present invention means the compound is not in a cell or organism and the compound is separated from some or all of the components that typically accompany it in nature.

As used herein, the term “pure” in connection with an isolated sample of a compound of the present invention means the isolated sample contains at least 60% by weight of the compound. Preferably, the isolated sample contains at least 70% by weight of the compound. More preferably, the isolated sample contains at least 80% by weight of the compound. Even more preferably, the isolated sample contains at least 90% by weight of the compound. Most preferably, the isolated sample contains at least 95% by weight of the compound. The purity of an isolated sample of a compound of the present invention may be assessed by a number of methods or a combination of them; e.g., thin-layer, preparative or flash chromatography, mass spectrometry, HPLC, NMR analysis, and the like.

The term “heteroatom” is art-recognized and refers to an atom of any element other than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.

The term “alkyl” is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C₁-C₃₀ for straight chain, C₃-C₃₀ for branched chain), and alternatively, about 20 or fewer. Likewise, cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, 6 or 7 carbons in the ring structure.

Unless the number of carbons is otherwise specified, “lower alkyl” refers to an alkyl group, as defined above, but having from one to about ten carbons, alternatively from one to about six carbon atoms in its backbone structure. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths.

The term “aralkyl” is art-recognized and refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).

The terms “alkenyl” and “alkynyl” are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

The term “aryl” is art-recognized and refers to 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, naphthalene, anthracene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as “aryl heterocycles” or “heteroaromatics.” The aromatic ring may be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, —CF₃, —CN, or the like. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.

The terms ortho, meta and para are art-recognized and refer to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively. For example, the names 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

The terms “heterocyclyl”, “heteroaryl”, or “heterocyclic group” are art-recognized and refer to 3- to about 10-membered ring structures, alternatively 3- to about 7-membered rings, whose ring structures include one to four heteroatoms. Heterocycles may also be polycycles. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxanthene, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, piperonyl, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, —CF₃, —CN, or the like.

The term “optionally substituted” refers to a chemical group, such as alkyl, cycloalkyl aryl, and the like, wherein one or more hydrogen may be replaced with a substituent as described herein, including but not limited to halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, —CF₃, —CN, or the like.

The terms “polycyclyl” or “polycyclic group” are art-recognized and refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are “fused rings”. Rings that are joined through non-adjacent atoms are termed “bridged” rings. Each of the rings of the polycycle may be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, —CF₃, —CN, or the like.

The term “carbocycle” is art-recognized and refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.

The term “nitro” is art-recognized and refers to —NO₂; the term “halogen” is art-recognized and refers to —F, —Cl, —Br or —I; the term “sulfhydryl” is art-recognized and refers to —SH; the term “hydroxyl” means —OH; and the term “sulfonyl” is art-recognized and refers to —SO₂ ⁻. “Halide” designates the corresponding anion of the halogens, and “pseudohalide” has the definition set forth on 560 of Advanced Inorganic Chemistry by Cotton and Wilkinson.

The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas:

wherein R50, R51 and R52 each independently represent a hydrogen, an alkyl, an alkenyl, —(CH₂)_(m)—R61, or R50 and R51, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. In other embodiments, R50 and R51 (and optionally R52) each independently represent a hydrogen, an alkyl, an alkenyl, or —(CH₂)_(m)—R61. Thus, the term “alkylamine” includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R50 and R51 is an alkyl group.

The term “acylamino” is art-recognized and refers to a moiety that may be represented by the general formula:

wherein R50 is as defined above, and R54 represents a hydrogen, an alkyl, an alkenyl or —(CH₂)_(m)—R61, where m and R61 are as defined above.

The term “amido” is art recognized as an amino-substituted carbonyl and includes a moiety that may be represented by the general formula:

wherein R50 and R51 are as defined above. Certain embodiments of the amide in the present invention will not include imides which may be unstable.

The term “alkylthio” refers to an alkyl group, as defined above, having a sulfur radical attached thereto. In certain embodiments, the “alkylthio” moiety is represented by one of —S-alkyl, —S-alkenyl, —S-alkynyl, and —S—(CH₂)_(m)—R61, wherein m and R61 are defined above. Representative alkylthio groups include methylthio, ethyl thio, and the like.

The term “carboxyl” is art recognized and includes such moieties as may be represented by the general formulas:

wherein X50 is a bond or represents an oxygen or a sulfur, and R55 and R56 represents a hydrogen, an alkyl, an alkenyl, —(CH₂)_(m)—R61 or a pharmaceutically acceptable salt, R56 represents a hydrogen, an alkyl, an alkenyl or —(CH₂)_(m)—R61, where m and R61 are defined above. Where X50 is an oxygen and R55 or R56 is not hydrogen, the formula represents an “ester”. Where X50 is an oxygen, and R55 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R55 is a hydrogen, the formula represents a “carboxylic acid”. Where X50 is an oxygen, and R56 is hydrogen, the formula represents a “formate”. In general, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a “thiolcarbonyl” group. Where X50 is a sulfur and R55 or R56 is not hydrogen, the formula represents a “thiolester.” Where X50 is a sulfur and R55 is hydrogen, the formula represents a “thiolcarboxylic acid.” Where X50 is a sulfur and R56 is hydrogen, the formula represents a “thiolformate.” On the other hand, where X50 is a bond, and R55 is not hydrogen, the above formula represents a “ketone” group. Where X50 is a bond, and R55 is hydrogen, the above formula represents an “aldehyde” group.

The term “carbamoyl” refers to —O(C═O)NRR′, where R and R′ are independently H, aliphatic groups, aryl groups or heteroaryl groups.

The term “oxo” refers to a carbonyl oxygen (═O).

The terms “oxime” and “oxime ether” are art-recognized and refer to moieties that may be represented by the general formula:

wherein R75 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or —(CH₂)_(m)—R61. The moiety is an “oxime” when R is H; and it is an “oxime ether” when R is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or —(CH₂)_(m)—R61.

The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. An “ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of —O-alkyl, —O-alkenyl, —O-alkynyl, —O—(CH₂)_(m)—R61, where m and R61 are described above.

The term “sulfonate” is art recognized and refers to a moiety that may be represented by the general formula:

in which R57 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.

The term “sulfate” is art recognized and includes a moiety that may be represented by the general formula:

in which R57 is as defined above.

The term “sulfonamido” is art recognized and includes a moiety that may be represented by the general formula:

in which R50 and R56 are as defined above.

The term “sulfamoyl” is art-recognized and refers to a moiety that may be represented by the general formula:

in which R50 and R51 are as defined above.

The term “sulfonyl” is art-recognized and refers to a moiety that may be represented by the general formula:

in which R58 is one of the following: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

The term “sulfoxido” is art-recognized and refers to a moiety that may be represented by the general formula:

in which R58 is defined above.

The term “phosphoryl” is art-recognized and may in general be represented by the formula:

wherein Q50 represents S or O, and R59 represents hydrogen, a lower alkyl or an aryl. When used to substitute, e.g., an alkyl, the phosphoryl group of the phosphorylalkyl may be represented by the general formulas:

wherein Q50 and R59, each independently, are defined above, and Q51 represents O, S or N. When Q50 is S, the phosphoryl moiety is a “phosphorothioate”.

The term “phosphoramidite” is art-recognized and may be represented in the general formulas:

wherein Q51, R50, R51 and R59 are as defined above.

The term “phosphonamidite” is art-recognized and may be represented in the general formulas:

wherein Q51, R50, R51 and R59 are as defined above, and R60 represents a lower alkyl or an aryl.

Analogous substitutions may be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.

The definition of each expression, e.g., alkyl, m, n, and the like, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.

The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively. The terms triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, p-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively. A more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled “Standard List of Abbreviations.”

Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, polymers of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, E- and Z-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.

It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.

The term “substituted” is also contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents may be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

The phrase “protecting group” as used herein means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. Examples of nitrogen protecting groups include an amide (—NRC(═O)R) or a urethane (—NRC(═O)OR), for example, as: a methyl amide (—NHC(═O)CH₃); a benzyloxy amide (—NHC(═O)OCH₂C₆H₅NHCbz); as a t-butoxy amide (—NHC(═O)OC(CH₃)₃, —NHBoc); a 2-biphenyl-2-propoxy amide (—NHC(═O)OC(CH₃)₂C₆H₄C₆H₅NHBoc), as a 9-fluorenylmethoxy amide (—NHFmoc), as a 6-nitroveratryloxy amide (—NHNvoc), as a 2-trimethylsilylethyloxy amide (—NHTeoc), as a 2,2,2-trichloroethyloxy amide (—NHTroc), as an allyloxy amide (—NHAlloc), as a 2-(phenylsulfonyl)ethyloxy amide (—NHPsec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical. The field of protecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2^(nd) ed.; Wiley: New York, 1991). Protected forms of the inventive compounds are included within the scope of this invention.

The term “pharmaceutically acceptable salt” or “salt” refers to a salt of one or more compounds. Suitable pharmaceutically acceptable salts of compounds include acid addition salts, such as those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and also those formed with organic acids such as maleic acid. For example, acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, salicylic, tartaric, bitartaric, ascorbic, maleic, besylic, fumaric, gluconic, glucuronic, formic, glutamic, methanesulfonic, ethanesulfonic, benzenesulfonic, lactic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid, and related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephathalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.

Where the compounds carry one or more acidic moieties, pharmaceutically acceptable salts may be formed by treatment of a solution of the compound with a solution of a pharmaceutically acceptable base. Suitable bases for forming pharmaceutically acceptable salts with acidic functional groups include, but are not limited to, hydroxides and carbonates of alkali metals such as sodium, potassium, and lithium; alkaline earth metal such as calcium and magnesium; and other metals, such as aluminum and zinc. Suitable bases also include ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N,N-di alkyl-N-(hydroxy alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like.

Certain compounds of the invention and their salts may exist in more than one crystalline form (i.e., polymorph); the present invention includes each of the crystal forms and mixtures thereof.

Certain compounds of the invention and their salts may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.

Certain compounds of the invention may contain one or more chiral centers, and exist in different optically active forms. When compounds of the invention contain one chiral center, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers, such as racemic mixtures thereof. The enantiomers may be resolved by methods known to those skilled in the art; for example, enantiomers may be resolved by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example, via enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support; suitable include chiral supports (e.g., silica with a bound chiral ligand) or in the presence of a chiral solvent. Where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step may be used to liberate the desired purified enantiomer. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.

When a compound of the invention contains more than one chiral center, it may exist in diastereoisomeric forms. The diastereoisomeric compounds may be separated by methods known to those skilled in the art (for example, chromatography or crystallization) and the individual enantiomers may be separated as described above. The present invention includes the various diastereoisomers of compounds of the invention, and mixtures thereof. Compounds of the invention may exist in different tautomeric forms or as different geometric isomers, and the present invention includes each tautomer and/or geometric isomer of compounds of the invention, and mixtures thereof. For example, any olefins present in the compounds may exist as either the E- or Z-geometric isomers or a mixture thereof unless stated otherwise. Compounds of the invention may exist in zwitterionic form. The present invention includes each zwitterionic form of compounds of the invention, and mixtures thereof.

As used herein the term “pro-drug” refers to an agent, which is converted into the parent drug in vivo by some physiological chemical process (e.g., a prodrug on being brought to the physiological pH is converted to the desired drug form). Pro-drugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmacological compositions over the parent drug. An example, without limitation, of a pro-drug would be a compound of the present invention wherein it is administered as an ester (the “pro-drug”) to facilitate transmittal across a cell membrane where water solubility is not beneficial, but then it is metabolically hydrolyzed to the carboxylic acid once inside the cell where water solubility is beneficial. Pro-drugs have many useful properties. For example, a pro-drug may be more water soluble than the ultimate drug, thereby facilitating intravenous administration of the drug. A pro-drug may also have a higher level of oral bioavailability than the ultimate drug. After administration, the prodrug is enzymatically or chemically cleaved to deliver the ultimate drug in the blood or tissue.

Exemplary pro-drugs release an amine of a compound of the invention wherein the free hydrogen of an amine or alcohol is replaced by (C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyl-oxymethyl, N—(C₁-C₆)alkoxycarbonylamino-methyl, succinoyl, (C₁-C₆)alkanoyl, α-amino(C₁-C₄)alkanoyl, arylactyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl wherein said α-aminoacyl moieties are independently any of the naturally occurring L-amino acids found in proteins, —P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from detachment of the hydroxyl of the hemiacetal of a carbohydrate).

Other exemplary pro-drugs upon cleavage release a corresponding free acid, and such hydrolyzable ester-forming residues of the compounds of this invention include but are not limited to carboxylic acid substituents (e.g., —(CH₂)C(O)OH or a moiety that contains a carboxylic acid) wherein the free hydrogen is replaced by (C₁-C₄)alkyl, (C₂-C₁₂)alkanoyloxymethyl, (C₄-C₉)1-(alkanoyloxy)ethyl, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl), carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)-alkylcarbamoyl-(C₁-C₂)alkyl and piperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

The term “subject” as used herein, refers to an animal, typically a mammal or a human, that will be or has been the object of treatment, observation, and/or experiment. When the term is used in conjunction with administration of a compound or drug, then the subject has been the object of treatment, observation, and/or administration of the compound or drug.

The terms “co-administration” and “co-administering” refer to both concurrent administration (administration of two or more therapeutic agents at the same time) and time varied administration (administration of one or more therapeutic agents at a time different from that of the administration of an additional therapeutic agent or agents), as long as the therapeutic agents are present in the patient to some extent at the same time.

The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a cell culture, tissue system, animal, or human that is being sought by a researcher, veterinarian, clinician, or physician, which includes alleviation of the symptoms of the disease, condition, or disorder being treated.

The term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

The term “pharmaceutically acceptable carrier” refers to a medium that is used to prepare a desired dosage form of a compound. A pharmaceutically acceptable carrier can include one or more solvents, diluents, or other liquid vehicles; dispersion or suspension aids; surface active agents; isotonic agents; thickening or emulsifying agents; preservatives; solid binders; lubricants; and the like. Remington's Pharmaceutical Sciences, Fifteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1975) and Handbook of Pharmaceutical Excipients, Third Edition, A. H. Kibbe ed. (American Pharmaceutical Assoc. 2000), disclose various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof.

Compounds

An aspect of the invention relates to a compound of formula 1:

or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence: W and X are independently oxygen or sulfur; Z¹, Z² and Z³ are independently C—R²⁰ or N, provided that at least one of Z¹ and Z² is N; R¹ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —COR⁶, —C(O)OR⁶, —SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —[C(R⁴)₂]_(p)—R⁵; R² and R³ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶, —SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), —P(O)(OR⁶)(OR⁷); or R² and R³ are joined together to form an optionally substituted heterocyclic ring; R⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl; R⁵ is selected from the group consisting of aryl, heteroaryl, heterocyclyl, —N(R⁸)(R⁹), —N(R⁸)COR⁹, —N(R⁸)C(O)OR⁹, —N(R⁸)SO₂(R⁹), —CON(R⁸)(R⁹), —OC(O)N(R⁸)—(R⁹), —SO₂N(R⁸)(R⁹), —OC(O)OR⁸, —COOR⁸, —C(O)N(OH)(R⁸), —OS(O)₂OR⁸, —S(O)₂OR⁸, —S(O)₂R⁸, —OR⁸, —COR⁸, —OP(O)(OR⁸)(OR⁸), —P(O)(OR⁸)(OR⁸) and —N(R⁸)P(O)(OR⁹)(OR⁹); R⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; R⁷ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R⁶ and R⁷ are joined together to form a heterocyclic ring; R⁸ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; R⁹ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R⁸ and R⁹ are joined together to form a heterocyclic ring; R²⁰ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, halo, haloalkyl, trifluoromethyl, fluoroalkyl, perfluoroalkyl, thio, cyano, hydroxy, methoxy, alkoxy, phenoxy, aryloxy, heteroaryloxy, carboxyl, alkoxycarbonyl, acyl, nitro, amino, alkylamino, arylamino, heteroarylamino, amido, acylamino, sulfate, sulfonate, sulfonyl, sulfoxido, sulfonamido, sulfamoyl, —[C(R⁴)₂]_(p)—R⁵, NR¹⁴R¹⁵, OR¹⁶, O—[C(R⁴)₂]_(p)—R⁵, NR¹⁴—[C(R⁴)₂]_(p)—R⁵ and SR¹⁶; R¹⁴ and R¹⁵ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]—R⁵, —COR⁶, —C(O)OR⁶, —SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —P(O)(OR⁶)(OR⁷); or R¹⁴ and R¹⁵ are joined together to form an optionally substituted heterocyclic ring; R¹⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, and —C(O)N(R⁶)(R⁷); and p is 1, 2, 3, 4, 5, or 6;

wherein any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted.

In one embodiment, W and X are oxygen.

In one embodiment, Z¹ and Z² are nitrogen; and Z³ is C—R²⁰.

In one embodiment, Z¹, Z² and Z³ are nitrogen.

In one embodiment, Z¹ is nitrogen; and Z² and Z³ are each C—R²⁰.

In one embodiment, Z² is nitrogen; and Z¹ and Z³ are each C—R²⁰.

In one embodiment, R¹ is hydrogen.

In one embodiment, R¹ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, and —[C(R⁴)₂]_(p)—R⁵.

In one embodiment, W and X are oxygen, Z¹ and Z² are each nitrogen, Z³ is C—R²⁰ and R¹ is hydrogen.

In one embodiment, R² and R³ are joined together to form an optionally substituted heterocyclic ring.

In one embodiment, the optionally substituted heterocyclic ring is selected from the group consisting of piperazinyl, homopiperizinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, 1,4-diazepan-5-onyl and quinolinyl.

In one embodiment, R² and R³ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶, —SO₂(R⁶), —C(O)N(R⁶)(R⁷), and —SO₂N(R⁶)(R⁷), wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl may be optionally substituted.

In one embodiment, R² is —[C(R⁴)₂]_(p)—R⁵, and R³ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —COR⁶, —C(O)OR⁶, —SO₂(R⁶), —C(O)N(R⁶)(R⁷), and —SO₂N(R⁶)(R⁷), wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl may be optionally substituted.

In one embodiment, R⁵ is aryl or heteroaryl, each of which may be optionally substituted.

In one embodiment, R⁵ is —N(R⁸)(R⁹).

In one embodiment, R⁴ is hydrogen.

In one embodiment, R²⁰ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, haloalkyl, trifluoromethyl, carboxyl, alkoxycarbonyl, acyl, nitro, amido, acylamino, sulfonamido, —[C(R⁴)₂]_(p)—R⁵; NR¹⁴R¹⁵, OR¹⁶, and SR¹⁶.

In one embodiment, R²⁰ is hydrogen.

An aspect of the invention relates to compound of formula 2:

or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence: R¹ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —COR⁶, —C(O)OR⁶, —SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —[C(R⁴)₂]_(p)—R⁵; R² and R³ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶, —SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷)—P(O)(OR⁶)(OR⁷); or R² and R³ are joined together to form an optionally substituted heterocyclic ring; R⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl; R⁵ is selected from the group consisting of aryl, heteroaryl, heterocyclyl, —N(R⁸)(R⁹), —N(R⁸)COR⁹, —N(R⁸)C(O)OR⁹, —N(R)SO₂(R⁹), —CON(R⁸)(R⁹), —OC(O)N(R⁸)—(R⁹), —SO₂N(R⁸)(R⁹), —OC(O)OR⁸, —COOR⁸, —C(O)N(OH)(R⁸), —OS(O)₂OR⁸, —S(O)₂OR⁸, —S(O)₂R⁸, —OR⁸, —COR⁸, —OP(O)(OR⁸)(OR⁹), —P(O)(OR⁸)(OR⁹) and —N(R⁸)P(O)(OR⁹)(OR⁹); R⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; R⁷ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl, or R⁶ and R⁷ are joined together to form a heterocyclic ring; R⁸ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; R⁹ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R⁸ and R⁹ are joined together to form a heterocyclic ring; R²⁰ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, halo, haloalkyl, trifluoromethyl, fluoroalkyl, perfluoroalkyl, thio, cyano, hydroxy, methoxy, alkoxy, phenoxy, aryloxy, heteroaryloxy, carboxyl, alkoxycarbonyl, acyl, nitro, amino, alkylamino, arylamino, heteroarylamino, amido, acylamino, sulfate, sulfonate, sulfonyl, sulfoxido, sulfonamido, sulfamoyl, —[C(R⁴)₂]_(p)—R⁵, NR¹⁴R¹⁵, OR¹⁶, and SR¹⁶; R¹⁴ and R¹⁵ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶, —SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —P(O)(OR⁶)(OR⁷); or R¹⁴ and R¹⁵ are joined together to form an optionally substituted heterocyclic ring; R¹⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, and —C(O)N(R⁶)(R⁷); and p is 1, 2, 3, 4, 5, or 6;

wherein any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted.

In one embodiment, R¹ is hydrogen.

In one embodiment, R²⁰ is selected from the group consisting of hydrogen, alkyl, trifluoromethyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —[C(R⁴)₂]_(p)—R⁵, NR¹⁴R¹⁵, OR¹⁶, and SR¹⁶.

In one embodiment, R²⁰ is hydrogen.

In one embodiment, R² and R³ are joined together to form an optionally substituted heterocyclic ring.

In one embodiment, R² and R³ are joined together to form an optionally substituted heterocyclic ring selected from the group consisting of:

wherein, independently for each occurrence: R¹⁰ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR¹², —C(O)OR¹², —SO₂(R¹²)—SO₂N(R¹²)(R¹³), —P(O)(OR¹²)(OR¹³); R¹² and R¹³ are selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R¹² and R¹³ are joined together to form a heterocyclic ring; R¹¹ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, haloalkyl, thio, cyano, hydroxyalkyl, alkoxy, alkylalkoxy, alkylthio, nitro, cyano, —N(R¹⁷)(R¹⁸), —N(R¹⁷)COR¹⁸, —N(R¹⁷)C(O)OR¹⁸, —N(R¹⁷)SO₂(R¹⁸), —CON(R¹⁷)(R¹⁸), —OC(O)N(R¹⁷)—(R¹⁸), —SO₂N(R¹⁷)(R¹⁸), —OC(O)OR¹⁷, —COOR¹⁷, —C(O)N(OH)(R¹⁷), —OS(O)₂OR¹⁷, —S(O)₂OR¹⁷, —S(O)₂R¹⁷, —OR¹⁷, —COR¹⁷, —OP(O)(OR¹⁷)(OR¹⁸), —P(O)(OR¹⁷)(OR¹⁸), —N(R¹⁷)P(O)(OR¹⁸)(OR¹⁸), and —[C(R⁴)₂]_(p)—R⁵; R¹⁷ and R¹⁸ selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R¹⁷ and R¹⁸ are joined together to form a heterocyclic ring; and n is 0, 1, 2, or 3;

wherein any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted.

In one embodiment, R¹⁰ is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, heterocyclyl, —[C(R⁴)₂]_(p)—R⁵, —COR¹², —C(O)OR¹², and —SO₂(R¹²);

wherein any one of the aforementioned alkyl, aryl, heteroaryl, and heterocyclyl may be optionally substituted.

In one embodiment, n is 0.

In one embodiment, n is 1.

In one embodiment, R¹¹ is selected from the group consisting of alkyl, heterocyclyl, cyano, hydroxyalkyl, —N(R¹⁷)(R¹⁸), —CON(R¹⁷)(R¹⁸), and —[C(R⁴)₂]^(p)—R⁵;

wherein any of the aforementioned alkyl and heterocyclyl may be optionally substituted.

In one embodiment, R² and R³ are joined together to form an optionally substituted heterocyclic ring of the formula:

In one embodiment, n is 0 or 1.

In one embodiment, R² and R³ are joined together to form an optionally substituted heterocyclic ring of the formula:

In one embodiment, R² and R³ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶, —SO₂(R⁶), —C(O)N(R⁶)(R⁷), and —SO₂N(R⁶)(R⁷), wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl may be optionally substituted.

In one embodiment, R³ is —[C(R⁴)₂]_(p)—R⁵.

In one embodiment, R² is optionally substituted alkyl.

In one embodiment, R⁴ is hydrogen.

In one embodiment, R⁴ is hydroxy.

In one embodiment, R⁵ is aryl, heteroaryl, heterocyclyl, each of which may be optionally substituted.

In one embodiment, p is 1, 2 or 3.

In one embodiment, R⁵ is selected from the group consisting of —N(R⁸)(R⁹), —N(R⁸)COR⁹, —N(R⁸)C(O)OR⁹, —N(R⁸)SO₂(R⁹), —CON(R⁸)(R⁹), —OC(O)N(R⁸)—(R⁹), —SO₂N(R⁸)(R⁹), —OC(O)OR⁸, —COOR⁸, —C(O)N(OH)(R⁸), —OS(O)₂OR⁸, —S(O)₂OR⁸, —S(O)₂R⁸, —OR⁸, —COR⁸, —OP(O)(OR⁸)(OR⁸), —P(O)(OR⁸)(OR⁸) and —N(R⁸)P(O)(OR⁹)(OR⁹).

In one embodiment, R⁵ is —N(R⁸)(R⁹).

An aspect of the invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

An aspect of the invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

Any one of the aforementioned compounds may exist as the E-geometric isomer, the Z-geometric isomer, or mixtures thereof. For example, in one embodiment,

in the aforementioned structures represents the E-isomer of the particular compound. In another embodiment,

represents the Z-isomer of the particular compound. In yet another embodiment,

represents a mixture of E and Z isomers of the particular compound.

In one embodiment, any one of the aforementioned compounds is an inhibitor of CK1γ1, CK1γ2, or CK1γ3.

In one embodiment, any one of the aforementioned compounds is an inhibitor of CK2.

In one embodiment, any one of the aforementioned compounds is an inhibitor of the Wnt pathway.

In one embodiment, any one of the aforementioned compounds is an inhibitor of the JAK/STAT pathway.

In one embodiment, any one of the aforementioned compounds is an inhibitor of the mTOR pathway.

In one embodiment, any one of the aforementioned compounds is a mediator of Pgp degradation and/or drug efflux.

In one embodiment, any one of the aforementioned compounds is an inhibitor of the TGFβ pathway.

In some embodiments, the compound has an IC₅₀ of less than 5000 nM for CK1γ1, CK1γ2, or CK1γ3.

In some embodiments, the compound has an IC₅₀ of less than 1000 nM for CK1γ1, CK1γ2, or CK1γ3.

In some embodiments, the compound has an IC₅₀ of less than 500 nM for CK1γ1, CK1γ2, or CK1γ3.

In one embodiment, any one of the aforementioned compounds is an inhibitor of CK2.

In one embodiment, the compound has an IC₅₀ of less than 5000 nM for CK2.

In one embodiment, the compound has an IC₅₀ of less than 1000 nM for CK2.

In one embodiment, the compound has an IC₅₀ of less than 500 nM for CK2.

In one embodiment, any on of the aforementioned compounds is an inhibitor of PIM1, PIM2, or PIM3.

In one embodiment, the compound has an IC₅₀ of less than 5000 nM for PIM1, PIM2 or PIM3.

In one embodiment, the compound has an IC₅₀ of less than 1000 nM for PIM1, PIM2 or PIM3.

In one embodiment, the compound has an IC₅₀ of less than 500 nM for PIM1, PIM2 or PIM3.

General Synthetic Schemes

General synthetic schemes that were utilized to prepare compounds disclosed in this application are described below. For example, compounds of the invention may be prepared as shown in Scheme I:

Alternatively, the compounds of the invention can be made as shown in Scheme II:

Yet another method of making the compounds disclosed herein is depicted in Scheme III:

PROPHETIC EMBODIMENTS

Certain compounds of the invention could be made in accordance with the above schemes by reacting an amine (Reactant A) with the hydantoin core (Reactant B). Non-limiting prophetic examples of Reactant A and Reactant B are shown in Table 1 and Table 2, respectively.

TABLE 1 Reactant A Prophetic Examples. Reactant A #1 Structure

Molecular Weight 162.232 Molecular Formula C₁₀H₁₄N₂ Chemical name 1-phenylpiperazine Reactant A #2 Structure

Molecular Weight 163.22 Molecular Formula C₉H₁₃N₃ Chemical name 1-(pyridin-3-yl)piperazine Reactant A #3 Structure

Molecular Weight 164.208 Molecular Formula C₈H₁₂N₄ Chemical name 5-(piperazin-1-yl)pyrimidine Reactant A #4 Structure

Molecular Weight 164.208 Molecular Formula C₈H₁₂N₄ Chemical name 2-(piperazin-1-yl)pyrimidine Reactant A #5 Structure

Molecular Weight 205.256 Molecular Formula C₁₁H₁₅N₃O Chemical name N-phenylpiperazine-1-carboxamide Reactant A #6 Structure

Molecular Weight 197.32 Molecular Formula C₁₁H₂₃N₃ Chemical name 1-(1-ethylpiperidin-4-yl)piperazine Reactant A #7 Structure

Molecular Weight 177.246 Molecular Formula C₁₀H₁₅N₃ Chemical name 1-(pyridin-4-yl)-1,4-diazepane Reactant A #8 Structure

Molecular Weight 217.267 Molecular Formula C₁₂H₁₅N₃O Chemical name 2-(1,4-diazepan-1-yl)benzo[d]oxazole Reactant A #9 Structure

Molecular Weight 219.283 Molecular Formula C₁₂H₁₇N₃O Chemical name N-phenyl-1,4-diazepane-1-carboxamide Reactant A #10 Structure

Molecular Weight 261.366 Molecular Formula C₁₄H₂₃N₅ Chemical name 1-(6-methyl-2-(pyrrolidin-1-yl)pyrimidin-4-yl)- 1,4-diazepane Reactant A #11 Structure

Molecular Weight 130.231 Molecular Formula C₇H₁₈N₂ Chemical name N1,N1-diethyl-N2-methylethane-1,2-diamine Reactant A #12 Structure

Molecular Weight 251.305 Molecular Formula C₁₁H₁₃N₃O₂S Chemical name N-(2-aminoethyl)isoquinoline-5-sulfonamide Reactant A #13 Structure

Molecular Weight 164.204 Molecular Formula C₉H₁₂N₂O Chemical name N-(2-aminoethyl)benzamide Reactant A #14 Structure

Molecular Weight 189.214 Molecular Formula C₁₀H₁₁N₃O Chemical name 2-(2-aminoethyl)quinazolin-4(3H)-one Reactant A #15 Structure

Molecular Weight 190.242 Molecular Formula C₁₁H₁₄N₂O Chemical name phenyl(piperazin-1-yl)methanone Reactant A #16 Structure

Molecular Weight 226.295 Molecular Formula C₁₀H₁₄N₂O₂S Chemical name 1-(phenylsulfonyl)piperazine Reactant A #17 Structure

Molecular Weight 216.279 Molecular Formula C₁₃H₁₆N₂O Chemical name (hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)(phenyl)methanone Reactant A #18 Structure

Molecular Weight 252.333 Molecular Formula C₁₂H₁₆N₂O₂S Chemical name 2-(phenylsulfonyl)octahydropyrrolo[3,4-c]pyrrole Reactant A #19 Structure

Molecular Weight 231.294 Molecular Formula C₁₃H₁₇N₃O Chemical name N-phenylhexahydropyrrolo[3,4-c]pyrrole- 2(1H)-carboxamide Reactant A #20 Structure

Molecular Weight 217.267 Molecular Formula C₁₂H₁₅N₃O Chemical name N-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxamide Reactant A #21 Structure

Molecular Weight 202.252 Molecular Formula C₁₂H₁₄N₂O Chemical name phenyl(2,6-diazaspiro[3.3]heptan-2-yl)methanone Reactant A #22 Structure

Molecular Weight 238.306 Molecular Formula C₁₁H₁₄N₂O₂S Chemical name 2-(phenylsulfonyl)-2,6-diazaspiro[3.3]heptane

TABLE 2 Reactant B Prophetic Examples. Reactant B #1 Structure

Molecular Formula C₁₂H₁₁ClN₄O₃S Molecular Weight 326.759 Chemical name (Z)-5-((2-chloro-6-morpholinopyrimidin-4- yl)methylene)thiazolidine-2,4-dione Reactant B #2 Structure

Molecular Formula C₁₃H₁₄ClN₅O₂S Molecular Weight 339.801 Chemical name (Z)-5-((2-chloro-6-(4-methylpiperazin-1-yl)pyrimidin- 4-yl)methylene)thiazolidine-2,4-dione Reactant B #3 Structure

Molecular Formula C₁₆H₁₃ClN₄O₂S Molecular Weight 360.818 Chemical name (Z)-5-((6-(benzyl(methyl)amino)-2-chloropyrimidin- 4-yl)methylene)thiazolidine-2,4-dione Reactant B #4 Structure

Molecular Formula C₁₁H₁₁ClN₄O₃S Molecular Weight 314.748 Chemical name (Z)-5-((2-chloro-6-((2- hydroxyethyl)(methyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione Reactant B #5 Structure

Molecular Formula C₁₅H₁₁ClN₄O₂S Molecular Weight 346.791 Chemical name (Z)-5-((2-chloro-6-(methyl(phenyl)amino)pyrimidin- 4-yl)methylene)thiazolidine-2,4-dione Reactant B #6 Structure

Molecular Formula C₁₃H₈ClN₃O₄S Molecular Weight 337.738 Chemical name (Z)-5-((2-chloro-6-(furan-2-ylmethoxy)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione Reactant B #7 Structure

Molecular Formula C₁₄H₈ClN₃O₃S Molecular Weight 333.75 Chemical name (Z)-5-((2-chloro-6-phenoxypyrimidin-4- yl)methylene)thiazolidine-2,4-dione Reactant B #8 Structure

Molecular Formula C₁₅H₁₀ClN₃O₃S Molecular Weight 347.776 Chemical name (Z)-5-((6-(benzyloxy)-2-chloropyrimidin-4- yl)methylene)thiazolidine-2,4-dione Reactant B #9 Structure

Molecular Formula C₁₁H₁₀ClN₃O₄S Molecular Weight 315.733 Chemical name (Z)-5-((2-chloro-6-(2-methoxyethoxy)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione Reactant B #10 Structure

Molecular Formula C₁₂H₁₃ClN₄O₃S Molecular Weight 328.775 Chemical name (Z)-5-((2-chloro-6-(2-(dimethylamino)ethoxy) pyrimidin-4-yl)methylene)thiazolidine-2,4-dione Reactant B #11 Structure

Molecular Formula C₈H₄ClN₃O₂S Molecular Weight 241.654 Chemical name (Z)-5-((2-chloropyrimidin-4-yl)methylene) thiazolidine-2,4-dione Reactant B #12 Structure

Molecular Formula C₇H₃ClN₄O₂S Molecular Weight 242.642 Chemical name (Z)-5-((4-chloro-1,3,5-triazin-2-yl)methylene) thiazolidine-2,4-dione

Additional prophetic embodiments of the invention that may be made in accordance with the above reaction schemes using Reactants A and B are listed in Table 3. The geometric isomers listed in Table 3 are believed to reflect the actual geometry of the prophetic compounds If they were to be made; however, final structural assignments may only be made if the compounds are synthesized and subjected to appropriate 2D NMR experiments. Further, although the compounds are listed as the “Z” geometric isomer, both the E and Z geometric isomers and mixtures thereof are contemplated.

TABLE 3 Additional prophetic embodiments of the invention. Mol. Reactant No. Chemical Name Formula Weight A B 1 (Z)-5-((6-morpholino-2-(4-phenylpiperazin-1- C₂₂H₂₄N₆O₃S 452.529 1 1 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 2 (Z)-5-((6-morpholino-2-(4-(pyridin-3-yl)piperazin-1- C₂₁H₂₃N₇O₃S 453.517 2 1 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 3 (Z)-5-((6-morpholino-2-(4-(pyrimidin-5-yl)piperazin- C₂₀H₂₂N₈O₃S 454.505 3 1 1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 4 (Z)-5-((6-morpholino-2-(4-(pyrimidin-2-yl)piperazin- C₂₀H₂₂N₈O₃S 454.505 4 1 1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 5 (Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₃H₂₅N₇O₄S 495.554 5 1 morpholinopyrimidin-2-yl)-N-phenylpiperazine-1- carboxamide 6 (Z)-5-((2-(4-(1-ethylpiperidin-4-yl)piperazin-1-yl)-6- C₂₃H₃₃N₇O₃S 487.618 6 1 morpholinopyrimidin-4-yl)methylene)thiazolidine-2,4- dione 7 (Z)-5-((6-morpholino-2-(4-(pyridin-4-yl)-1,4-diazepan- C₂₂H₂₅N₇O₃S 467.544 7 1 1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 8 (Z)-5-((2-(4-(benzo[d]oxazol-2-yl)-1,4-diazepan-1-yl)- C₂₄H₂₅N₇O₄S 507.565 8 1 6-morpholinopyrimidin-4-yl)methylene)thiazolidine- 2,4-dione 9 (Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₄H₂₇N₇O₄S 509.581 9 1 morpholinopyrimidin-2-yl)-N-phenyl-1,4-diazepane-1- carboxamide 10 (Z)-5-((2-(4-(6-methyl-2-(pyrrolidin-1-yl)pyrimidin-4- C₂₆H₃₃N₉O₃S 551.664 10 1 yl)-1,4-diazepan-1-yl)-6-morpholinopyrimidin-4- yl)methylene)thiazolidine-2,4-dione 11 (Z)-5-((2-((2-(diethylamino)ethyl)(methyl)amino)-6- C₁₉H₂₈N₆O₃S 420.529 11 1 morpholinopyrimidin-4-yl)methylene)thiazolidine-2,4- dione 12 (Z)-N-(2-((4-((2,4-dioxotmazolidin-5-ylidene)methyl)- C₂₃H₂₃N₇O₅S₂ 541.603 12 1 6-morpholinopyrimidin-2-yl)amino)ethyl)isoquinoline- 5-sulfonamide 13 (Z)-N-(2-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₂₁H₂₂N₆O₄S 454.502 13 1 6-morpholinopyrimidin-2-yl)amino)ethyl)benzamide 14 (Z)-5-((6-morpholino-2-((2-(4-oxo-3,4- C₂₂H₂₁N₇O₄S 479.512 14 1 dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 15 (Z)-5-((2-(4-benzoylpiperazin-1-yl)-6- C₂₃H₂₄N₆O₄S 480.539 15 1 morpholinopyrimidin-4-yl)methylene)thiazolidine-2,4- dione 16 (Z)-5-((6-morpholino-2-(4-(phenylsulfonyl)piperazin- C₂₂H₂₄N₆O₅S₂ 516.593 16 1 1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 17 (Z)-5-((2-(5-benzoylhexahydropyrrolo[3,4-c]pyrrol- C₂₅H₂₆N₆O₄S 506.577 17 1 2(1H)-yl)-6-morpholinopyrimidin-4- yl)methylene)thiazolidine-2,4-dione 18 (Z)-5-((6-morpholino-2-(5- C₂₄H₂₆N₆O₅S₂ 542.63 18 1 (phenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 19 (Z)-5-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₅H₂₇N₇O₄S 521.591 19 1 morpholinopyrimidin-2-yl)-N- phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxamide 20 (Z)-6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₄H₂₅N₇O₄S 507.565 20 1 morpholinopyrimidin-2-yl)-N-phenyl-2,6- diazaspiro[3.3]heptane-2-carboxamide 21 (Z)-5-((2-(6-benzoyl-2,6-diazaspiro[3.3]heptan-2-yl)- C₂₄H₂₄N₆O₄S 492.55 21 1 6-morpholinopyrimidin-4-yl)methylene)thiazolidine- 2,4-dione 22 (Z)-5-((6-morpholino-2-(6-(phenylsulfonyl)-2,6- C₂₃H₂₄N₆O₅S₂ 528.604 22 1 diazaspiro[3.3]heptan-2-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 23 (Z)-5-((6-(4-methylpiperazin-1-yl)-2-(4- C₂₃H₂₇N₇O₂S 465.571 1 2 phenylpiperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 24 (Z)-5-((6-(4-methylpiperazin-1-yl)-2-(4-(pyridin-3- C₂₂H₂₆N₈O₂S 466.559 2 2 yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 25 (Z)-5-((6-(4-methylpiperazin-1-yl)-2-(4-(pyrimidin-5- C₂₁H₂₅N₉O₂S 467.547 3 2 yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 26 (Z)-5-((6-(4-methylpiperazin-1-yl)-2-(4-(pyrimidin-2- C₂₁H₂₅N₉O₂S 467.547 4 2 yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 27 (Z)-4-(4-((2,4-dioxotmazolidin-5-ylidene)methyl)-6-(4- C₂₄H₂₈N₈O₃S 508.596 5 2 methylpiperazin-1-yl)pyrimidin-2-yl)-N- phenylpiperazine-1-carboxamide 28 (Z)-5-((2-(4-(1-ethylpiperidin-4-yl)piperazin-1-yl)-6- C₂₄H₃₆N₈O₂S 500.66 6 2 (4-methylpiperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 29 (Z)-5-((6-(4-methylpiperazin-1-yl)-2-(4-(pyridin-4-yl)- C₂₃H₂₈N₈O₂S 480.586 7 2 1,4-diazepan-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 30 (Z)-5-((2-(4-(benzo[d]oxazol-2-yl)-1,4-diazepan-1-yl)- C₂₅H₂₈N₈O₃S 520.607 8 2 6-(4-methylpiperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 31 (Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6-(4- C₂₅H₃₀N₈O₃S 522.623 9 2 methylpiperazin-1-yl)pyrimidin-2-yl)-N-phenyl-1,4- diazepane-1-carboxamide 32 (Z)-5-((2-(4-(6-methyl-2-(pyrrolidin-1-yl)pyrimidin-4- C₂₇H₃₆N₁₀O₂S 564.706 10 2 yl)-1,4-diazepan-1-yl)-6-(4-methylpiperazin-1- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 33 (Z)-5-((2-((2-(diethylamino)ethyl)(methyl)amino)-6- C₂₀H₃₁N₇O₂S 433.571 11 2 (4-methylpiperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 34 (Z)-N-(2-((4-((2,4-dioxotmazolidin-5-ylidene)methyl)- C₂₄H₂₆N₈O₄S₂ 554.644 12 2 6-(4-methylpiperazin-1-yl)pyrimidin-2- yl)amino)ethyl)isoquinoline-5-sulfonamide 35 (Z)-N-(2-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₂₂H₂₅N₇O₃S 467.544 13 2 6-(4-methylpiperazin-1-yl)pyrimidin-2- yl)amino)ethyl)benzamide 36 (Z)-5-((6-(4-methylpiperazin-1-yl)-2-((2-(4-oxo-3,4- C₂₃H₂₄N₈O₃S 492.553 14 2 dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 37 (Z)-5-((2-(4-benzoylpiperazin-1-yl)-6-(4- C₂₄H₂₇N₇O₃S 493.581 15 2 methylpiperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 38 (Z)-5-((6-(4-methylpiperazin-1-yl)-2-(4- C₂₃H₂₇N₇O₄S₂ 529.635 16 2 (phenylsulfonyl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 39 (Z)-5-((2-(5-benzoylhexahydropyrrolo[3,4-c]pyrrol- C₂₆H₂₉N₇O₃S 519.619 17 2 2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 40 (Z)-5-((6-(4-methylpiperazin-1-yl)-2-(5- C₂₅H₂₉N₇O₄S₂ 555.672 18 2 (phenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 41 (Z)-5-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6-(4- C₂₆H₃₀N₈O₃S 534.633 19 2 methylpiperazin-1-yl)pyrimidin-2-yl)-N- phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxamide 42 (Z)-6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6-(4- C₂₅H₂₈N₈O₃S 520.607 20 2 methylpiperazin-1-yl)pyrimidin-2-yl)-N-phenyl-2,6- diazaspiro[3.3]heptane-2-carboxamide 43 (Z)-5-((2-(6-benzoyl-2,6-diazaspiro[3.3]heptan-2-yl)- C₂₅H₂₇N₇O₃S 505.592 21 2 6-(4-methylpiperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 44 (Z)-5-((6-(4-methylpiperazin-1-yl)-2-(6- C₂₄H₂₇N₇O₄S₂ 541.646 22 2 (phenylsulfonyl)-2,6-diazaspiro[3.3]heptan-2- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 45 (Z)-5-((6-(benzyl(methyl)amino)-2-(4- C₂₆H₂₆N₆O₂S 486.589 1 3 phenylpiperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 46 (Z)-5-((6-(benzyl(methyl)amino)-2-(4-(pyridin-3- C₂₅H₂₅N₇O₂S 487.577 2 3 yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 47 (Z)-5-((6-(benzyl(methyl)amino)-2-(4-(pyrimidin-5- C₂₄H₂₄N₈O₂S 488.565 3 3 yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 48 (Z)-5-((6-(benzyl(methyl)amino)-2-(4-(pyrimidin-2- C₂₄H₂₄N₈O₂S 488.565 4 3 yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 49 (Z)-4-(4-(benzyl(methyl)amino)-6-((2,4- C₂₇H₂₇N₇O₃S 529.613 5 3 dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)-N- phenylpiperazine-1-carboxamide 50 (Z)-5-((6-(benzyl(methyl)amino)-2-(4-(1- C₂₇H₃₅N₇O₂S 521.678 6 3 ethylpiperidin-4-yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 51 (Z)-5-((6-(benzyl(methyl)amino)-2-(4-(pyridin-4-yl)- C₂₆H₂₇N₇O₂S 501.603 7 3 1,4-diazepan-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 52 (Z)-5-((2-(4-(benzo[d]oxazol-2-yl)-1,4-diazepan-1-yl)- C₂₈H₂₇N₇O₃S 541.624 8 3 6-(benzyl(methyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 53 (Z)-4-(4-(benzyl(methyl)amino)-6-((2,4- C₂₈H₂₉N₇O₃S 543.64 9 3 dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)-N- phenyl-1,4-diazepane-1-carboxamide 54 (Z)-5-((6-(benzyl(methyl)amino)-2-(4-(6-methyl-2- C₃₀H₃₅N₉O₂S 585.723 10 3 (pyrrolidin-1-yl)pyrimidin-4-yl)-1,4-diazepan-1- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 55 (Z)-5-((6-(benzyl(methyl)amino)-2-((2- C₂₃H₃₀N₆O₂S 454.588 11 3 (diethylamino)ethyl)(methyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 56 (Z)-N-(2-((4-(benzyl(methyl)amino)-6-((2,4- C₂₇H₂₅N₇O₄S₂ 575.662 12 3 dioxothiazolidin-5-ylidene)methyl)pyrimidin-2- yl)amino)ethyl)isoquinoline-5-sulfonamide 57 (Z)-N-(2-((4-(benzyl(methyl)amino)-6-((2,4- C₂₅H₂₄N₆O₃S 488.561 13 3 dioxothiazolidin-5-ylidene)methyl)pyrimidin-2- yl)amino)ethyl)benzamide 58 (Z)-5-((6-(benzyl(methyl)amino)-2-((2-(4-oxo-3,4- C₂₆H₂₃N₇O₃S 513.571 14 3 dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 59 (Z)-5-((2-(4-benzoylpiperazin-1-yl)-6- C₂₇H₂₆N₆O₃S 514.599 15 3 (benzyl(methyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 60 (Z)-5-((6-(benzyl(methyl)amino)-2-(4- C₂₆H₂₆N₆O₄S₂ 550.652 16 3 (phenylsulfonyl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 61 (Z)-5-((2-(5-benzoylhexahydropyrrolo[3,4-c]pyrrol- C₂₉H₂₈N₆O₃S 540.636 17 3 2(1H)-yl)-6-(benzyl(methyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 62 (Z)-5-((6-(benzyl(methyl)amino)-2-(5- C₂₈H₂₈N₆O₄S₂ 576.69 18 3 (phenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 63 (Z)-5-(4-(benzyl(methyl)amino)-6-((2,4- C₂₉H₂₉N₇O₃S 555.651 19 3 dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)-N- phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxamide 64 (Z)-6-(4-(benzyl(methyl)amino)-6-((2,4- C₂₈H₂₇N₇O₃S 541.624 20 3 dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)-N- phenyl-2,6-diazaspiro[3.3]heptane-2-carboxamide 65 (Z)-5-((2-(6-benzoyl-2,6-diazaspiro[3.3]heptan-2-yl)- C₂₈H₂₆N₆O₃S 526.609 21 3 6-(benzyl(methyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 66 (Z)-5-((6-(benzyl(methyl)amino)-2-(6- C₂₇H₂₆N₆O₄S₂ 562.663 22 3 (phenylsulfonyl)-2,6-diazaspiro[3.3]heptan-2- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 67 (Z)-5-((6-((2-hydroxyethyl)(methyl)amino)-2-(4- C₂₁H₂₄N₆O₃S 440.519 1 4 phenylpiperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 68 (Z)-5-((6-((2-hydroxyethyl)(methyl)amino)-2-(4- C₂₀H₂₃N₇O₃S 441.507 2 4 (pyridin-3-yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 69 (Z)-5-((6-((2-hydroxyethyl)(methyl)amino)-2-(4- C₁₉H₂₂N₈O₃S 442.495 3 4 (pyrimidin-5-yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 70 (Z)-5-((6-((2-hydroxyethyl)(methyl)amino)-2-(4- C₁₉H₂₂N₈O₃S 442.495 4 4 (pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 71 (Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₂H₂₅N₇O₄S 483.543 5 4 ((2-hydroxyethyl)(methyl)amino)pyrimidin-2-yl)-N- phenylpiperazine-1-carboxamide 72 (Z)-5-((2-(4-(1-ethylpiperidin-4-yl)piperazin-1-yl)-6- C₂₂H₃₃N₇O₃S 475.608 6 4 ((2-hydroxyethyl)(methyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 73 (Z)-5-((6-((2-hydroxyethyl)(methyl)amino)-2-(4- C₂₁H₂₅N₇O₃S 455.533 7 4 (pyridin-4-yl)-1,4-diazepan-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 74 (Z)-5-((2-(4-(benzo[d]oxazol-2-yl)-1,4-diazepan-1-yl)- C₂₃H₂₅N₇O₄S 495.554 8 4 6-((2-hydroxyethyl)(methyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 75 (Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₃H₂₇N₇O₄S 497.57 9 4 ((2-hydroxyethyl)(methyl)amino)pyrimidin-2-yl)-N- phenyl-1,4-diazepane-1-carboxamide 76 (Z)-5-((6-((2-hydroxyethyl)(methyl)amino)-2-(4-(6- C₂₅H₃₃N₉O₃S 539.653 10 4 methyl-2-(pyrrolidin-1-yl)pyrimidin-4-yl)-1,4- diazepan-1-yl)pyrimidin-4-yl)methylene)thiazolidine- 2,4-dione 77 (Z)-5-((2-((2-(diethylamino)ethyl)(methyl)amino)-6- C₁₈H₂₈N₆O₃S 408.518 11 4 ((2-hydroxyethyl)(methyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 78 (Z)-N-(2-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₂₂H₂₃N₇O₅S₂ 529.592 12 4 6-((2-hydroxyethyl)(methyl)amino)pyrimidin-2- yl)amino)ethyl)isoquinoline-5-sulfonamide 79 (Z)-N-(2-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₂₀H₂₂N₆O₄S 442.491 13 4 6-((2-hydroxyethyl)(methyl)amino)pyrimidin-2- yl)amino)ethyl)benzamide 80 (Z)-5-((6-((2-hydroxyethyl)(methyl)amino)-2-((2-(4- C₂₁H₂₁N₇O₄S 467.501 14 4 oxo-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidin-4-yl)methylene)thiazolidine- 2,4-dione 81 (Z)-5-((2-(4-benzoylpiperazin-1-yl)-6-((2- C₂₂H₂₄N₆O₄S 468.529 15 4 hydroxyethyl)(methyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 82 (Z)-5-((6-((2-hydroxyethyl)(methyl)amino)-2-(4- C₂₁H₂₄N₆O₅S₂ 504.582 16 4 (phenylsulfonyl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 83 (Z)-5-((2-(5-benzoylhexahydropyrrolo[3,4-c]pyrrol- C₂₄H₂₆N₆O₄S 494.566 17 4 2(1H)-yl)-6-((2- hydroxyethyl)(methyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 84 (Z)-5-((6-((2-hydroxyethyl)(methyl)amino)-2-(5- C₂₃H₂₆N₆O₅S₂ 530.62 18 4 (phenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 85 (Z)-5-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₄H₂₇N₇O₄S 509.581 19 4 ((2-hydroxyethyl)(methyl)amino)pyrimidin-2-yl)-N- phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxamide 86 (Z)-6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₃H₂₅N₇O₄S 495.554 20 4 ((2-hydroxyethyl)(methyl)amino)pyrimidin-2-yl)-N- phenyl-2,6-diazaspiro[3.3]heptane-2-carboxamide 87 (Z)-5-((2-(6-benzoyl-2,6-diazaspiro[3.3]heptan-2-yl)- C₂₃H₂₄N₆O₄S 480.539 21 4 6-((2-hydroxyethyl)(methyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 88 (Z)-5-((6-((2-hydroxyethyl)(methyl)amino)-2-(6- C₂₂H₂₄N₆O₅S₂ 516.593 22 4 (phenylsulfonyl)-2,6-diazaspiro[3.3]heptan-2- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 89 (Z)-5-((6-(methyl(phenyl)amino)-2-(4- C₂₅H₂₄N₆O₂S 472.562 1 5 phenylpiperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 90 (Z)-5-((6-(methyl(phenyl)amino)-2-(4-(pyridin-3- C₂₄H₂₃N₇O₂S 473.55 2 5 yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 91 (Z)-5-((6-(methyl(phenyl)amino)-2-(4-(pyrimidin-5- C₂₃H₂₂N₈O₂S 474.538 3 5 yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 92 (Z)-5-((6-(methyl(phenyl)amino)-2-(4-(pyrimidin-2- C₂₃H₂₂N₈O₂S 474.538 4 5 yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 93 (Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₆H₂₅N₇O₃S 515.587 5 5 (methyl(phenyl)amino)pyrimidin-2-yl)-N- phenylpiperazine-1-carboxamide 94 (Z)-5-((2-(4-(1-ethylpiperidin-4-yl)piperazin-1-yl)-6- C₂₆H₃₃N₇O₂S 507.651 6 5 (methyl(phenyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 95 (Z)-5-((6-(methyl(phenyl)amino)-2-(4-(pyridin-4-yl)- C₂₅H₂₅N₇O₂S 487.577 7 5 1,4-diazepan-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 96 (Z)-5-((2-(4-(benzo[d]oxazol-2-yl)-1,4-diazepan-1-yl)- C₂₇H₂₅N₇O₃S 527.598 8 5 6-(methyl(phenyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 97 (Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₇H₂₇N₇O₃S 529.613 9 5 (methyl(phenyl)amino)pyrimidin-2-yl)-N-phenyl-1,4- diazepane-1-carboxamide 98 (Z)-5-((6-(methyl(phenyl)amino)-2-(4-(6-methyl-2- C₂₉H₃₃N₉O₂S 571.696 10 5 (pyrrolidin-1-yl)pyrimidin-4-yl)-1,4-diazepan-1- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 99 (Z)-5-((2-((2-(diethylamino)ethyl)(methyl)amino)-6- C₂₂H₂₈N₆O₂S 440.562 11 5 (methyl(phenyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 100 (Z)-N-(2-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₂₆H₂₃N₇O₄S₂ 561.635 12 5 6-(methyl(phenyl)amino)pyrimidin-2- yl)amino)ethyl)isoquinoline-5-sulfonamide 101 (Z)-N-(2-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₂₄H₂₂N₆O₃S 474.535 13 5 6-(methyl(phenyl)amino)pyrimidin-2- yl)amino)ethyl)benzamide 102 (Z)-5-((6-(methyl(phenyl)amino)-2-((2-(4-oxo-3,4- C₂₅H₂₁N₇O₃S 499.544 14 5 dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 103 (Z)-5-((2-(4-benzoylpiperazin-1-yl)-6- C₂₆H₂₄N₆O₃S 500.572 15 5 (methyl(phenyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 104 (Z)-5-((6-(methyl(phenyl)amino)-2-(4- C₂₅H₂₄N₆O₄S₂ 536.626 16 5 (phenylsulfonyl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 105 (Z)-5-((2-(5-benzoylhexahydropyrrolo[3,4-c]pyrrol- C₂₈H₂₆N₆O₃S 526.609 17 5 2(1H)-yl)-6-(methyl(phenyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 106 (Z)-5-((6-(methyl(phenyl)amino)-2-(5- C₂₇H₂₆N₆O₄S₂ 562.663 18 5 (phenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 107 (Z)-5-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₈H₂₇N₇O₃S 541.624 19 5 (methyl(phenyl)amino)pyrimidin-2-yl)-N- phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxamide 108 (Z)-6-(4-((2,4-dioxothiazolidm-5-ylidene)methyl)-6- C₂₇H₂₅N₇O₃S 527.598 20 5 (methyl(phenyl)amino)pyrimidin-2-yl)-N-phenyl-2,6- diazaspiro[3.3]heptane-2-carboxamide 109 (Z)-5-((2-(6-benzoyl-2,6-diazaspiro[3.3]heptan-2-yl)- C₂₇H₂₄N₆O₃S 512.583 21 5 6-(methyl(phenyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 110 (Z)-5-((6-(methyl(phenyl)amino)-2-(6- C₂₆H₂₄N₆O₄S₂ 548.637 22 5 (phenylsulfonyl)-2,6-diazaspiro[3.3]heptan-2- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 111 (Z)-5-((6-(furan-2-ylmethoxy)-2-(4-phenylpiperazin-1- C₂₃H₂₁N₅O₄S 463.509 1 6 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 112 (Z)-5-((6-(furan-2-ylmethoxy)-2-(4-(pyridin-3- C₂₂H₂₀N₆O₄S 464.497 2 6 yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 113 (Z)-5-((6-(furan-2-ylmethoxy)-2-(4-(pyrimidin-5- C₂₁H₁₉N₇O₄S 465.485 3 6 yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 114 (Z)-5-((6-(furan-2-ylmethoxy)-2-(4-(pyrimidin-2- C₂₁H₁₉N₇O₄S 465.485 4 6 yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 115 (Z)-4-(4-((2,4-dioxothiazolidm-5-ylidene)methyl)-6- C₂₄H₂₂N₆O₅S 506.534 5 6 (furan-2-ylmethoxy)pyrimidin-2-yl)-N- phenylpiperazine-1-carboxamide 116 (Z)-5-((2-(4-(1-ethylpiperidin-4-yl)piperazin-1-yl)-6- C₂₄H₃₀N₆O₄S 498.598 6 6 (furan-2-ylmethoxy)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 117 (Z)-5-((6-(furan-2-ylmethoxy)-2-(4-(pyridin-4-yl)-1,4- C₂₃H₂₂N₆O₄S 478.524 7 6 diazepan-1-yl)pyrimidin-4-yl)methylene)thiazolidine- 2,4-dione 118 (Z)-5-((2-(4-(benzo[d]oxazol-2-yl)-1,4-diazepan-1-yl)- C₂₅H₂₂N₆O₅S 518.544 8 6 6-(furan-2-ylmethoxy)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 119 (Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₅H₂₄N₆O₅S 520.56 9 6 (furan-2-ylmethoxy)pyrimidin-2-yl)-N-phenyl-1,4- diazepane-1-carboxamide 120 (Z)-5-((6-(furan-2-ylmethoxy)-2-(4-(6-methyl-2- C₂₇H₃₀N₈O₄S 562.643 10 6 (pyrrolidin-1-yl)pyrimidin-4-yl)-1,4-diazepan-1- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 121 (Z)-5-((2-((2-(diethylamino)ethyl)(methyl)amino)-6- C₂₀H₂₅N₅O₄S 431.509 11 6 (furan-2-ylmethoxy)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 122 (Z)-N-(2-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₂₄H₂₀N₆O₆S₂ 552.582 12 6 6-(furan-2-ylmethoxy)pyrimidin-2- yl)amino)ethyl)isoquinoline-5-sulfonamide 123 (Z)-N-(2-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₂₂H₁₉N₅O₅S 465.482 13 6 6-(furan-2-ylmethoxy)pyrimidin-2- yl)amino)ethyl)benzamide 124 (Z)-5-((6-(furan-2-ylmethoxy)-2-((2-(4-oxo-3,4- C₂₃H₁₈N₆O₅S 490.491 14 6 dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 125 (Z)-5-((2-(4-benzoylpiperazin-1-yl)-6-(furan-2- C₂₄H₂₁N₅O₅S 491.519 15 6 ylmethoxy)pyrimidin-4-yl)methylene)thiazolidine-2,4- dione 126 (Z)-5-((6-(furan-2-ylmethoxy)-2-(4- C₂₃H₂₁N₅O₆S₂ 527.573 16 6 (phenylsulfonyl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 127 (Z)-5-((2-(5-benzoylhexahydropyrrolo[3,4-c]pyrrol- C₂₆H₂₃N₅O₅S 517.556 17 6 2(1H)-yl)-6-(furan-2-ylmethoxy)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 128 (Z)-5-((6-(furan-2-ylmethoxy)-2-(5- C₂₅H₂₃N₅O₆S₂ 553.61 18 6 (phenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 129 (Z)-5-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₆H₂₄N₆O₅S 532.571 19 6 (furan-2-ylmethoxy)pyrimidin-2-yl)-N- phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxamide 130 (Z)-6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₅H₂₂N₆O₅S 518.544 20 6 (furan-2-ylmethoxy)pyrimidin-2-yl)-N-phenyl-2,6- diazaspiro[3.3]heptane-2-carboxamide 131 (Z)-5-((2-(6-benzoyl-2,6-diazaspiro[3.3]heptan-2-yl)- C₂₅H₂₁N₅O₅S 503.53 21 6 6-(furan-2-ylmethoxy)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 132 (Z)-5-((6-(furan-2-ylmethoxy)-2-(6-(phenylsulfonyl)- C₂₄H₂₁N₅O₆S₂ 539.583 22 6 2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 133 (Z)-5-((6-phenoxy-2-(4-phenylpiperazin-1- C₂₄H₂₁N₅O₃S 459.52 1 7 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 134 (Z)-5-((6-phenoxy-2-(4-(pyridin-3-yl)piperazin-1- C₂₃H₂₀N₆O₃S 460.508 2 7 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 135 (Z)-5-((6-phenoxy-2-(4-(pyrimidin-5-yl)piperazin-1- C₂₂H₁₉N₇O₃S 461.496 3 7 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 136 (Z)-5-((6-phenoxy-2-(4-(pyrimidin-2-yl)piperazin-1- C₂₂H₁₉N₇O₃S 461.496 4 7 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 137 (Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₅H₂₂N₆O₄S 502.545 5 7 phenoxypyrimidin-2-yl)-N-phenylpiperazine-1- carboxamide 138 (Z)-5-((2-(4-(1-ethylpiperidin-4-yl)piperazin-1-yl)-6- C₂₅H₃₀N₆O₃S 494.609 6 7 phenoxypyrimidin-4-yl)methylene)thiazolidine-2,4- dione 139 (Z)-5-((6-phenoxy-2-(4-(pyridin-4-yl)-1,4-diazepan-1- C₂₄H₂₂N₆O₃S 474.535 7 7 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 140 (Z)-5-((2-(4-(benzo[d]oxazol-2-yl)-1,4-diazepan-1-yl)- C₂₆H₂₂N₆O₄S 514.556 8 7 6-phenoxypyrimidin-4-yl)methylene)thiazolidine-2,4- dione 141 (Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₆H₂₄N₆O₄S 516.572 9 7 phenoxypyrimidin-2-yl)-N-phenyl-1,4-diazepane-1- carboxamide 142 (Z)-5-((2-(4-(6-methyl-2-(pyrrolidin-1-yl)pyrimidin-4- C₂₈H₃₀N₈O₃S 558.655 10 7 yl)-1,4-diazepan-1-yl)-6-phenoxypyrimidin-4- yl)methylene)thiazolidine-2,4-dione 143 (Z)-5-((2-((2-(diethylamino)ethyl)(methyl)amino)-6- C₂₁H₂₅N₅O₃S 427.52 11 7 phenoxypyrimidin-4-yl)methylene)thiazolidine-2,4- dione 144 (Z)-N-(2-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₂₅H₂₀N₆O₅S₂ 548.594 12 7 6-phenoxypyrimidin-2-yl)amino)ethyl)isoquinoline-5- sulfonamide 145 (Z)-N-(2-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₂₃H₁₉N₅O₄S 461.493 13 7 6-phenoxypyrimidin-2-yl)amino)ethyl)benzamide 146 (Z)-5-((2-((2-(4-oxo-3,4-dihydroquinazolin-2- C₂₄H₁₈N₆O₄S 486.503 14 7 yl)ethyl)amino)-6-phenoxypyrimidin-4- yl)methylene)thiazolidine-2,4-dione 147 (Z)-5-((2-(4-benzoylpiperazin-1-yl)-6- C₂₅H₂₁N₅O₄S 487.53 15 7 phenoxypyrimidin-4-yl)methylene)thiazolidine-2,4- dione 148 (Z)-5-((6-phenoxy-2-(4-(phenylsulfonyl)piperazin-1- C₂₄H₂₁N₅O₅S₂ 523.584 16 7 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 149 (Z)-5-((2-(5-benzoylhexahydropyrrolo[3,4-c]pyrrol- C₂₇H₂₃N₅O₄S 513.568 17 7 2(1H)-yl)-6-phenoxypyrimidin-4- yl)methylene)thiazolidine-2,4-dione 150 (Z)-5-((6-phenoxy-2-(5- C₂₆H₂₃N₅O₅S₂ 549.621 18 7 (phenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 151 (Z)-5-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₇H₂₄N₆O₄S 528.582 19 7 phenoxypyrimidin-2-yl)-N- phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxamide 152 (Z)-6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6- C₂₆H₂₂N₆O₄S 514.556 20 7 phenoxypyrimidin-2-yl)-N-phenyl-2,6- diazaspiro[3.3]heptane-2-carboxamide 153 (Z)-5-((2-(6-benzoyl-2,6-diazaspiro[3.3]heptan-2-yl)- C₂₆H₂₁N₅O₄S 499.541 21 7 6-phenoxypyrimidin-4-yl)methylene)thiazolidine-2,4- dione 154 (Z)-5-((6-phenoxy-2-(6-(phenylsulfonyl)-2,6- C₂₅H₂₁N₅O₅S₂ 535.595 22 7 diazaspiro[3.3]heptan-2-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 155 (Z)-5-((6-(benzyloxy)-2-(4-phenylpiperazin-1- C₂₅H₂₃N₅O₃S 473.547 1 8 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 156 (Z)-5-((6-(benzyloxy)-2-(4-(pyridin-3-yl)piperazin-1- C₂₄H₂₂N₆O₃S 474.535 2 8 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 157 (Z)-5-((6-(benzyloxy)-2-(4-(pyrimidin-5-yl)piperazin- C₂₃H₂₁N₇O₃S 475.523 3 8 1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 158 (Z)-5-((6-(benzyloxy)-2-(4-(pyrimidin-2-yl)piperazin- C₂₃H₂₁N₇O₃S 475.523 4 8 1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 159 (Z)-4-(4-(benzyloxy)-6-((2,4-dioxothiazolidin-5- C₂₆H₂₄N₆O₄S 516.572 5 8 ylidene)methyl)pyrimidin-2-yl)-N-phenylpiperazine-1- carboxamide 160 (Z)-5-((6-(benzyloxy)-2-(4-(1-ethylpiperidin-4- C₂₆H₃₂N₆O₃S 508.636 6 8 yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 161 (Z)-5-((6-(benzyloxy)-2-(4-(pyridin-4-yl)-1,4- C₂₅H₂₄N₆O₃S 488.561 7 8 diazepan-1-yl)pyrimidin-4-yl)methylene)thiazolidine- 2,4-dione 162 (Z)-5-((2-(4-(benzo[d]oxazol-2-yl)-1,4-diazepan-1-yl)- C₂₇H₂4N₆O₄S 528.582 8 8 6-(benzyloxy)pyrimidin-4-yl)methylene)thiazolidine- 2,4-dione 163 (Z)-4-(4-(benzyloxy)-6-((2,4-dioxothiazolidin-5- C₂₇H₂₆N₆O₄S 530.598 9 8 ylidene)methyl)pyrimidin-2-yl)-N-phenyl-1,4- diazepane-1-carboxamide 164 (Z)-5-((6-(benzyloxy)-2-(4-(6-methyl-2-(pyrrolidin-1- C₂₉H₃₂N₈O₃S 572.681 10 8 yl)pyrimidin-4-yl)-1,4-diazepan-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 165 (Z)-5-((6-(benzyloxy)-2-((2- C₂₂H₂₇N₅O₃S 441.546 11 8 (diethylamino)ethyl)(methyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 166 (Z)-N-(2-((4-(benzyloxy)-6-((2,4-dioxothiazolidin-5- C₂₆H₂₂N₆O₅S₂ 562.62 12 8 ylidene)methyl)pyrimidin-2- yl)amino)ethyl)isoquinoline-5-sulfonamide 167 (Z)-N-(2-((4-(benzyloxy)-6-((2,4-dioxothiazolidin-5- C₂₄H₂₁N₅O₄S 475.52 13 8 ylidene)methyl)pyrimidin-2-yl)amino)ethyl)benzamide 168 (Z)-5-((6-(benzyloxy)-2-((2-(4-oxo-3,4- C₂₅H₂₀N₆O₄S 500.529 14 8 dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 169 (Z)-5-((2-(4-benzoylpiperazin-1-yl)-6- C₂₆H₂₃N₅O₄S 501.557 15 8 (benzyloxy)pyrimidin-4-yl)methylene)thiazolidine-2,4- dione 170 (Z)-5-((6-(benzyloxy)-2-(4-(phenylsulfonyl)piperazin- C₂₅H₂₃N₅O₅S₂ 537.611 16 8 1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 171 (Z)-5-((2-(5-benzoylhexahydropyrrolo[3,4-c]pyrrol- C₂₈H₂₅N₅O₄S 527.594 17 8 2(1H)-yl)-6-(benzyloxy)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 172 (Z)-5-((6-(benzyloxy)-2-(5- C₂₇H₂₅N₅O₅S₂ 563.648 18 8 (phenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 173 (Z)-5-(4-(benzyloxy)-6-((2,4-dioxothiazolidin-5- C₂₈H₂₆N₆O₄S 542.609 19 8 ylidene)methyl)pyrimidin-2-yl)-N- phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxamide 174 (Z)-6-(4-(benzyloxy)-6-((2,4-dioxothiazolidin-5- C₂₇H₂₄N₆O₄S 528.582 20 8 ylidene)methyl)pyrimidin-2-yl)-N-phenyl-2,6- diazaspiro[3.3]heptane-2-carboxamide 175 (Z)-5-((2-(6-benzoyl-2,6-diazaspiro[3.3]heptan-2-yl)- C₂₇H₂₃N₅O₄S 513.568 21 8 6-(benzyloxy)pyrimidin-4-yl)methylene)thiazolidine- 2,4-dione 176 (Z)-5-((6-(benzyloxy)-2-(6-(phenylsulfonyl)-2,6- C₂₆H₂₃N₅O₅S₂ 549.621 22 8 diazaspiro[3.3]heptan-2-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 177 (Z)-5-((6-(2-methoxyethoxy)-2-(4-phenylpiperazin-1- C₂₁H₂₃N₅O₄S 441.503 1 9 yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 178 (Z)-5-((6-(2-methoxyethoxy)-2-(4-(pyridin-3- C₂₀H₂₂N₆O₄S 442.491 2 9 yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 179 (Z)-5-((6-(2-methoxyethoxy)-2-(4-(pyrimidin-5- C₁₉H₂₁N₇O₄S 443.48 3 9 yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 180 (Z)-5-((6-(2-methoxyethoxy)-2-(4-(pyrimidin-2- C₁₉H₂₁N₇O₄S 443.48 4 9 yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 181 (Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6-(2- C₂₂H₂₄N₆O₅S 484.528 5 9 methoxyethoxy)pyrimidin-2-yl)-N-phenylpiperazine-1- carboxamide 182 (Z)-5-((2-(4-(1-ethylpiperidin-4-yl)piperazin-1-yl)-6- C₂₂H₃₂N₆O₄S 476.592 6 9 (2-methoxyethoxy)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 183 (Z)-5-((6-(2-methoxyethoxy)-2-(4-(pyridin-4-yl)-1,4- C₂₁H₂₄N₆O₄S 456.518 7 9 diazepan-1-yl)pyrimidin-4-yl)methylene)thiazolidine- 2,4-dione 184 (Z)-5-((2-(4-(benzo[d]oxazol-2-yl)-1,4-diazepan-1-yl)- C₂₃H₂₄N₆O₅S 496.539 8 9 6-(2-methoxyethoxy)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 185 (Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6-(2- C₂₃H₂₆N₆O₅S 498.555 9 9 methoxyethoxy)pyrimidin-2-yl)-N-phenyl-1,4- diazepane-1-carboxamide 186 (Z)-5-((6-(2-methoxyethoxy)-2-(4-(6-methyl-2- C₂₅H₃₂N₈O₄S 540.638 10 9 (pyrrolidin-1-yl)pyrimidin-4-yl)-1,4-diazepan-1- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 187 (Z)-5-((2-((2-(diethylamino)ethyl)(methyl)amino)-6- C₁₈H₂₇N₅O₄S 409.503 11 9 (2-methoxyethoxy)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 188 (Z)-N-(2-((4-((2,4-dioxotmazolidin-5-ylidene)methyl)- C₂₂H₂₂N₆O₆S₂ 530.577 12 9 6-(2-methoxyethoxy)pyrimidin-2- yl)amino)ethyl)isoquinoline-5-sulfonamide 189 (Z)-N-(2-((4-((2,4-dioxothiazolidm-5-ylidene)methyl)- C₂₀H₂₁N₅O₅S 443.476 13 9 6-(2-methoxyethoxy)pyrimidin-2- yl)amino)ethyl)benzarnide 190 (Z)-5-((6-(2-methoxyethoxy)-2-((2-(4-oxo-3,4- C₂₁H₂₀N₆O₅S 468.486 14 9 dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 191 (Z)-5-((2-(4-benzoylpiperazin-1-yl)-6-(2- C₂₂H₂₃N₅O₅S 469.514 15 9 methoxyethoxy)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 192 (Z)-5-((6-(2-methoxyethoxy)-2-(4- C₂₁H₂₃N₅O₆S₂ 505.567 16 9 (phenylsulfonyl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 193 (Z)-5-((2-(5-benzoylhexahydropyrrolo[3,4-c]pyrrol- C₂₄H₂₅N₅O₅S 495.551 17 9 2(1H)-yl)-6-(2-methoxyethoxy)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 194 (Z)-5-((6-(2-methoxyethoxy)-2-(5- C₂₃H₂₅N₅O₆S₂ 531.605 18 9 (phenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 195 (Z)-5-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6-(2- C₂₄H₂₆N₆O₅S 510.565 19 9 methoxyethoxy)pyrimidin-2-yl)-N- phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxamide 196 (Z)-6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6-(2- C₂₃H₂₄N₆O₅S 496.539 20 9 methoxyethoxy)pyrimidin-2-yl)-N-phenyl-2,6- diazaspiro[3.3]heptane-2-carboxamide 197 (Z)-5-((2-(6-benzoyl-2,6-diazaspiro[3.3]heptan-2-yl)- C₂₃H₂₃N₅O₅S 481.524 21 9 6-(2-methoxyethoxy)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 198 (Z)-5-((6-(2-methoxyethoxy)-2-(6-(phenylsulfonyl)- C₂₂H₂₃N₅O₆S₂ 517.578 22 9 2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 199 (Z)-5-((6-(2-(dimethylamino)ethoxy)-2-(4- C₂₂H₂₆N₆O₃S 454.545 1 10 phenylpiperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 200 (Z)-5-((6-(2-(dimethylamino)ethoxy)-2-(4-(pyridin-3- C₂₁H₂₅N₇O₃S 455.533 2 10 yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 201 (Z)-5-((6-(2-(dimethylamino)ethoxy)-2-(4-(pyrimidin- C₂₀H₂₄N₈O₃S 456.521 3 10 5-yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 202 (Z)-5-((6-(2-(dimethylamino)ethoxy)-2-(4-(pyrimidin- C₂₀H₂₄N₈O₃S 456.521 4 10 2-yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 203 (Z)-4-(4-(2-(dimethylamino)ethoxy)-6-((2,4- C₂₃H₂₇N₇O₄S 497.57 5 10 dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)-N- phenylpiperazine-1-carboxamide 204 (Z)-5-((6-(2-(dimethylamino)ethoxy)-2-(4-(1- C₂₃H₃₅N₇O₃S 489.634 6 10 ethylpiperidin-4-yl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 205 (Z)-5-((6-(2-(dimethylamino)ethoxy)-2-(4-(pyridin-4- C₂₂H₂₇N₇O₃S 469.56 7 10 yl)-1,4-diazepan-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 206 (Z)-5-((2-(4-(benzo[d]oxazol-2-yl)-1,4-diazepan-1-yl)- C₂₄H₂₇N₇O₄S 509.581 8 10 6-(2-(dimethylamino)ethoxy)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 207 (Z)-4-(4-(2-(dimethylamino)ethoxy)-6-((2,4- C₂₄H₂₉N₇O₄S 511.597 9 10 dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)-N- phenyl-1,4-diazepane-1-carboxamide 208 (Z)-5-((6-(2-(dimethylamino)ethoxy)-2-(4-(6-methyl- C₂₆H₃₅N₉O₃S 553.68 10 10 2-(pyrrolidin-1-yl)pyrimidin-4-yl)-1,4-diazepan-1- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 209 (Z)-5-((2-((2-(diethylamino)ethyl)(methyl)amino)-6- C₁₉H₃₀N₆O₃S 422.545 11 10 (2-(dimethylamino)ethoxy)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 210 (Z)-N-(2-((4-(2-(dimethylamino)ethoxy)-6-((2,4- C₂₃H₂₅N₇O₅S₂ 543.619 12 10 dioxothiazolidin-5-ylidene)methyl)pyrimidin-2- yl)amino)ethyl)isoquinoline-5-sulfonamide 211 (Z)-N-(2-((4-(2-(dimethylamino)ethoxy)-6-((2,4- C₂₁H₂₄N₆O₄S 456.518 13 10 dioxothiazolidin-5-ylidene)methyl)pyrimidin-2- yl)amino)ethyl)benzamide 212 (Z)-5-((6-(2-(dimethylamino)ethoxy)-2-((2-(4-oxo-3,4- C₂₂H₂₃N₇O₄S 481.528 14 10 dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 213 (Z)-5-((2-(4-benzoylpiperazin-1-yl)-6-(2- C₂₃H₂₆N₆O₄S 482.555 15 10 (dimethylamino)ethoxy)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 214 (Z)-5-((6-(2-(dimethylamino)ethoxy)-2-(4- C₂₂H₂₆N₆O₅S₂ 518.609 16 10 (phenylsulfonyl)piperazin-1-yl)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 215 (Z)-5-((2-(5-benzoylhexahydropyrrolo[3,4-c]pyrrol- C₂₅H₂₈N₆O₄S 508.593 17 10 2(1H)-yl)-6-(2-(dimethylamino)ethoxy)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 216 (Z)-5-((6-(2-(dimethylamino)ethoxy)-2-(5- C₂₄H₂₈N₆O₅S₂ 544.646 18 10 (phenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 217 (Z)-5-(4-(2-(dimethylamino)ethoxy)-6-((2,4- C₂₅H₂₉N₇O₄S 523.607 19 10 dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)-N- phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxamide 218 (Z)-6-(4-(2-(dimethylamino)ethoxy)-6-((2,4- C₂₄H₂₇N₇O₄S 509.581 20 10 dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)-N- phenyl-2,6-diazaspiro[3.3]heptane-2-carboxamide 219 (Z)-5-((2-(6-benzoyl-2,6-diazaspiro[3.3]heptan-2-yl)- C₂₄H₂₆N₆O₄S 494.566 21 10 6-(2-(dimethylamino)ethoxy)pyrimidin-4- yl)methylene)thiazolidine-2,4-dione 220 (Z)-5-((6-(2-(dimethylamino)ethoxy)-2-(6- C₂₃H₂₆N₆O₅S₂ 530.62 22 10 (phenylsulfonyl)-2,6-diazaspiro[3.3]heptan-2- yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione 221 (Z)-5-((4-(4-phenylpiperazin-1-yl)pyrimidin-2- C₁₈H₁₇N₅O₂S 367.425 1 11 yl)methylene)thiazolidine-2,4-dione 222 (Z)-5-((4-(4-(pyridin-3-yl)piperazin-1-yl)pyrimidin-2- C₁₇H₁₆N₆O₂S 368.413 2 11 yl)methylene)thiazolidine-2,4-dione 223 (Z)-5-((4-(4-(pyrimidin-5-yl)piperazin-1-yl)pyrimidin- C₁₆H₁₅N₇O₂S 369.401 3 11 2-yl)methylene)thiazolidine-2,4-dione 224 (Z)-5-((4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin- C₁₆H₁₅N₇O₂S 369.401 4 11 2-yl)methylene)thiazolidine-2,4-dione 225 (Z)-4-(2-((2,4-dioxothiazolidin-5- C₁₉H₁₈N₆O₃S 410.45 5 11 ylidene)methyl)pyrimidin-4-yl)-N-phenylpiperazine-1- carboxamide 226 (Z)-5-((4-(4-(1-ethylpiperidin-4-yl)piperazin-1- C₁₉H₂₆N₆O₂S 402.514 6 11 yl)pyrimidin-2-yl)methylene)thiazolidine-2,4-dione 227 (Z)-5-((4-(4-(pyridin-4-yl)-1,4-diazepan-1- C₁₈H₁₈N₆O₂S 382.44 7 11 yl)pyrimidin-2-yl)methylene)thiazolidine-2,4-dione 228 (Z)-5-((4-(4-(benzo[d]oxazol-2-yl)-1,4-diazepan-1- C₂₀H₁₈N₆O₃S 422.46 8 11 yl)pyrimidin-2-yl)methylene)thiazolidine-2,4-dione 229 (Z)-4-(2-((2,4-dioxothiazolidin-5- C₂₀H₂₀N₆O₃S 424.476 9 11 ylidene)methyl)pyrimidin-4-yl)-N-phenyl-1,4- diazepane-1-carboxamide 230 (Z)-5-((4-(4-(6-methyl-2-(pyrrolidin-1-yl)pyrimidin-4- C₂₂H₂₆N₈O₂S 466.559 10 11 yl)-1,4-diazepan-1-yl)pyrimidin-2- yl)methylene)thiazolidine-2,4-dione 231 (Z)-5-((4-((2- C₁₅H₂₁N₅O₂S 335.425 11 11 (diethylamino)ethyl)(methyl)amino)pyrimidin-2- yl)methylene)thiazolidine-2,4-dione 232 (Z)-N-(2-((2-((2,4-dioxothiazolidin-5- C₁₉H₁₆N₆O₄S₂ 456.498 12 11 ylidene)methyl)pyrimidin-4- yl)amino)ethyl)isoquinoline-5-sulfonamide 233 (Z)-N-(2-((2-((2,4-dioxothiazolidin-5- C₁₇H₁₅N₅O₃S 369.398 13 11 ylidene)methyl)pyrimidin-4-yl)amino)ethyl)benzamide 234 (Z)-5-((4-((2-(4-oxo-3,4-dihydroquinazolin-2- C₁₈H₁₄N₆O₃S 394.407 14 11 yl)ethyl)amino)pyrimidin-2-yl)methylene)thiazolidine- 2,4-dione 235 (Z)-5-((4-(4-benzoylpiperazin-1-yl)pyrimidin-2- C₁₉H₁₇N₅O₃S 395.435 15 11 yl)methylene)thiazolidine-2,4-dione 236 (Z)-5-((4-(4-(phenylsulfonyl)piperazin-1-yl)pyrimidin- C₁₈H₁₇N₅O₄S₂ 431.489 16 11 2-yl)methylene)thiazolidine-2,4-dione 237 (Z)-5-((4-(5-benzoylhexahydropyrrolo[3,4-c]pyrrol- C₂₁H₁₉N₅O₃S 421.472 17 11 2(1H)-yl)pyrimidin-2-yl)methylene)thiazolidine-2,4- dione 238 (Z)-5-((4-(5-(phenylsulfonyl)hexahydropyrrolo[3,4- C₂oH₁₉N₅O₄S₂ 457.526 18 11 c]pyrrol-2(1H)-yl)pyrimidin-2- yl)methylene)thiazolidine-2,4-dione 239 (Z)-5-(2-((2,4-dioxothiazolidin-5- C₂₁H₂₀N₆O₃S 436.487 19 11 ylidene)methyl)pyrimidin-4-yl)-N- phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxamide 240 (Z)-6-(2-((2,4-dioxothiazolidin-5- C₂₀H₁₈N₆O₃S 422.46 20 11 ylidene)methyl)pyrimidin-4-yl)-N-phenyl-2,6- diazaspiro[3.3]heptane-2-carboxamide 241 (Z)-5-((4-(6-benzoyl-2,6-diazaspiro[3.3]heptan-2- C₂₀H₁₇N₅O₃S 407.446 21 11 yl)pyrimidin-2-yl)methylene)thiazolidine-2,4-dione 242 (Z)-5-((4-(6-(phenylsulfonyl)-2,6- C₁₉H₁₇N₅O₄S₂ 443.499 22 11 diazaspiro[3.3]heptan-2-yl)pyrimidin-2- yl)methylene)thiazolidine-2,4-dione 243 (Z)-5-((4-(4-phenylpiperazin-1-yl)-1,3,5-triazin-2- C₁₇H₁₆N₆O₂S 368.413 1 12 yl)methylene)thiazolidine-2,4-dione 244 (Z)-5-((4-(4-(pyridin-3-yl)piperazin-1-yl)-1,3,5-triazin- C₁₆H₁₅N₇O₂S 369.401 2 12 2-yl)methylene)thiazolidine-2,4-dione 245 (Z)-5-((4-(4-(pyrimidin-5-yl)piperazin-1-yl)-1,3,5- C₁₅H₁₄N₈O₂S 370.389 3 12 triazin-2-yl)methylene)thiazolidine-2,4-dione 246 (Z)-5-((4-(4-(pyrimidin-2-yl)piperazin-1-yl)-1,3,5- C₁₅H₁₄N₈O₂S 370.389 4 12 triazin-2-yl)methylene)thiazolidine-2,4-dione 247 (Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₁₈H₁₇N₇O₃S 411.438 5 12 1,3,5-triazin-2-yl)-N-phenylpiperazine-1-carboxamide 248 (Z)-5-((4-(4-(1-ethylpiperidin-4-yl)piperazin-1-yl)- C₁₈H₂₅N₇O₂S 403.502 6 12 1,3,5-triazin-2-yl)methylene)thiazolidine-2,4-dione 249 (Z)-5-((4-(4-(pyridin-4-yl)-1,4-diazepan-1-yl)-1,3,5- C₁₇H₁₇N₇O₂S 383.428 7 12 triazin-2-yl)methylene)thiazolidine-2,4-dione 250 (Z)-5-((4-(4-(benzo[d]oxazol-2-yl)-1,4-diazepan-1-yl)- C₁₉H₁₇N₇O₃S 423.448 8 12 1,3,5-triazin-2-yl)methylene)thiazolidine-2,4-dione 251 (Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₁₉H₁₉N₇O₃S 425.464 9 12 1,3,5-triazin-2-yl)-N-phenyl-1,4-diazepane-1- carboxamide 252 (Z)-5-((4-(4-(6-methyl-2-(pyrrolidin-1-yl)pyrimidin-4- C₂₁H₂₅N₉O₂S 467.547 10 12 yl)-1,4-diazepan-1-yl)-1,3,5-triazin-2- yl)methylene)thiazolidine-2,4-dione 253 (Z)-5-((4-((2-(diethylamino)ethyl)(methyl)amino)- C₁₄H₂₀N₆O₂S 336.413 11 12 1,3,5-triazin-2-yl)methylene)thiazolidine-2,4-dione 254 (Z)-N-(2-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₁₈H₁₅N₇O₄S₂ 457.486 12 12 1,3,5-triazin-2-yl)amino)ethyl)isoquinoline-5- sulfonamide 255 (Z)-N-(2-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₁₆H₁₄N₆O₃S 370.386 13 12 1,3,5-triazin-2-yl)amino)ethyl)benzamide 256 (Z)-5-((4-((2-(4-oxo-3,4-dihydroquinazolin-2- C₁₇H₁₃N₇O₃S 395.395 14 12 yl)ethyl)amino)-1,3,5-triazin-2- yl)methylene)thiazolidine-2,4-dione 257 (Z)-5-((4-(4-benzoylpiperazin-1-yl)-1,3,5-triazin-2- C₁₈H₁₆N₆O₃S 396.423 15 12 yl)methylene)thiazolidine-2,4-dione 258 (Z)-5-((4-(4-(phenylsulfonyl)piperazin-1-yl)-1,3,5- C₁₇H₁₆N₆O₄S₂ 432.477 16 12 triazin-2-yl)methylene)thiazolidine-2,4-dione 259 (Z)-5-((4-(5-benzoylhexahydropyrrolo[3,4-c]pyrrol- C₂₀H₁₈N₆O₃S 422.46 17 12 2(1H)-yl)-1,3,5-triazin-2-yl)methylene)thiazolidine- 2,4-dione 260 (Z)-5-((4-(5-(phenylsulfonyl)hexahydropyrrolo[3,4- C₁₉H₁₈N₆O₄S₂ 458.514 18 12 c]pyrrol-2(1H)-yl)-1,3,5-triazin-2- yl)methylene)thiazolidine-2,4-dione 261 (Z)-5-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₂₀H₁₉N₇O₃S 437.475 19 12 1,3,5-triazin-2-yl)-N-phenylhexahydropyrrolo[3,4- c]pyrrole-2(lH)-carboxamide 262 (Z)-6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)- C₁₉H₁₇N₇O₃S 423.448 20 12 1,3,5-triazin-2-yl)-N-phenyl-2,6- diazaspiro[3.3]heptane-2-carboxamide 263 (Z)-5-((4-(6-benzoyl-2,6-diazaspiro[3.3]heptan-2-yl)- C₁₉H₁₆N₆O₃S 408.434 21 12 1,3,5-triazin-2-yl)methylene)thiazolidine-2,4-dione 264 (Z)-5-((4-(6-(phenylsulfonyl)-2,6- C₁₈H₁₆N₆O₄S₂ 444.487 22 12 diazaspiro[3.3]heptan-2-yl)-1,3,5-triazin-2- yl)methylene)thiazolidine-2,4-dione

In addition, it may be convenient or desirable to prepare, purify, and/or handle the active compound in a chemically protected form. The term “chemically protected form,” as used herein, pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions (i.e., they have been modified with a protecting group).

By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed without affecting the protected group; the protecting group may be removed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts, Wiley, 1991), and Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).

For example, a hydroxy group may be protected as an ether (—OR) or an ester (—OC(═O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl)ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (—OC(═O)CH₃, —OAc).

For example, an aldehyde or ketone group may be protected as an acetal or ketal, respectively, in which the carbonyl group (C(═O)) is converted to a diether (C(OR)₂), by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.

For example, an amine group may be protected, for example, as an amide (—NRC(═O)R) or a urethane (—NRC(═O)OR), for example, as: a methyl amide (—NHC(═O)CH₃); a benzyloxy amide (—NHC(═O)OCH₂C₆H₅NHCbz); as a t-butoxy amide (—NHC(═O)OC(CH₃)₃, —NHBoc); a 2-biphenyl-2-propoxy amide (—NHC(═O)OC(CH₃)₂C₆H₄C₆H₅NHBoc), as a 9-fluorenylmethoxy amide (—NHFmoc), as a 6-nitroveratryloxy amide (—NHNvoc), as a 2-trimethylsilylethyloxy amide (—NHTeoc), as a 2,2,2-trichloroethyloxy amide (—NHTroc), as an allyloxy amide (—NHAlloc), as a 2-(phenylsulfonyl)ethyloxy amide (—NHPsec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical.

For example, a carboxylic acid group may be protected as an ester or an amide, for example, as: a benzyl ester; a t-butyl ester; a methyl ester; or a methyl amide.

For example, a thiol group may be protected as a thioether (—SR), for example, as: a benzyl thioether; or an acetamidomethyl ether (—SCH₂NHC(═O)CH₃).

Pharmaceutical Compositions

One or more compounds of this invention can be administered to a mammal by themselves or in pharmaceutical compositions where they are mixed with suitable carriers or excipient(s) at doses to treat or ameliorate a disease or condition as described herein. Mixtures of these compounds can also be administered to the patient as a simple mixture or in suitable formulated pharmaceutical compositions. For example, one aspect of the invention relates to pharmaceutical composition comprising a therapeutically effective dose of a compound of formula I, or a pharmaceutically acceptable salt, solvate, enantiomer or stereoisomer thereof; and a pharmaceutically acceptable diluent or carrier.

Techniques for formulation and administration of the compounds of the instant application may be found in references well known to one of ordinary skill in the art, such as “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa., latest edition.

Suitable routes of administration may, for example, include oral, eyedrop, rectal, transmucosal, topical, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.

Alternatively, one may administer a compound in a local rather than a systemic manner, for example, via injection of the compound directly into an edematous site, often in a depot or sustained release formulation.

Furthermore, one may administer a compound in a targeted drug delivery system, for example, in a liposome coated with endothelial-cell-specific antibody.

The pharmaceutical compositions of the present invention may be manufactured, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.

Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.

For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants are used in the formulation appropriate to the barrier to be permeated. Such penetrants are generally known in the art.

For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.

For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

The compounds can be formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

Alternatively, the active ingredient may be in powder form for reconstitution before use with a suitable vehicle, e.g., sterile pyrogen-free water.

The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly or by intramuscular injection). Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (for example, as a sparingly soluble salt).

Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethysulfoxide also may be employed. Additionally, the compounds may be delivered using a sustained-release system, such as semi-permeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.

The pharmaceutical compositions may also comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers, such as polyethylene glycols.

Methods of Treatment

Provided herein are methods of modulating the activity of CK1 and subtypes thereof, CK2, the Wnt pathway, and/or the TGFβ pathway. Also provided herein are methods of treating or preventing conditions and diseases the course of which can be influenced by modulating the activity of CK1 (e.g., CK1γ), CK2, the Wnt pathway, and/or the TGFβ pathway. Such methods typically comprise administering to a subject in need thereof a therapeutically effective amount of a compound or composition of the invention.

Also provided herein are methods of modulating the activity of PIM, such as PIM 1, PIM 2 or PIM 3, the JAK/STAT pathway, and/or the mTOR pathway, and/or Pgp. Also provided herein are methods of treating or preventing conditions and diseases, the course of which can be influenced by modulating the activity of the PIMs, the JAK/STAT pathway, and/or the mTOR pathway, and/or Pgp. Such methods typically comprise administering to a subject in need thereof a therapeutically effective amount of a compound or composition of the invention.

Various diseases, such as cancers, inflammation, and inflammatory diseases (e.g., osteoarthritis and rheumatoid arthritis), and neurological conditions (e.g., Alzheimer's disease) and neurodegeneration can be treated by administration of modulators of CK1 (e.g., CK1γ), CK2, the Wnt pathway and/or the TGFβ pathway. Bone-related diseases and conditions, including osteoporosis and bone formation, also can be treated by administration of modulators of CK1 (e.g., CK1γ), CK2, the Wnt pathway and/or the TGFβ pathway. Bone restoration can be facilitated by administration of modulators of CK1 (e.g., CK1γ), CK2, the Wnt pathway and/or the TGFβ pathway. Additional conditions that can be treated by administration of modulators of CK1 (e.g., CK1γ), CK2, the Wnt pathway and/or the TGFβ pathway include hypoglycemia, metabolic syndrome and diabetes. Modulators of CK1 (e.g., CK1γ), CK2, the Wnt pathway and/or the TGFβ pathway are also useful for influencing apoptosis (e.g., increasing the rate of apoptosis in cancerous cells). Modulators of CK1 (e.g., CK1γ), CK2, the Wnt pathway and/or the TGFβ pathway are also useful in treatment or prevention of aberrant embryonic development.

Based at least on the fact that increased CK1γ has been found to be associated with certain cancers, a method for treating cancer in a subject comprises administering to the subject in need thereof a therapeutically effective amount of a compound that inhibits CK1γ. PIM1, PIM2, PIM3, the JAK/STAT pathway, and/or the mTOR pathway have also been found to be associated with certain cancers. Therefore, provided herein is a method for treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound that inhibits PIM1 and/or PIM2 and/or PIM3.

PIM1, PIM2, and PIM3 have also been associated with protecting Pgp from degradation, which can regulate drug efflux and drug resistance. Therefore, provided herein is a method for treating malignancies comprising administering to a subject in need thereof a therapeutically effective amount of a compound that inhibits PIM1 and/or PIM2 and/or PIM3 in conjunction with another drug, compound or material to abrogate resistance to the drug, compound or material.

The compounds described herein can be used for modulating cell proliferation, generally. Accordingly, diseases that may be treated include hyperproliferative diseases, such as benign cell growth and malignant cell growth.

Exemplary cancers that may be treated include leukemias, e.g., acute lymphoid leukemia and myeloid leukemia, and carcinomas, such as colorectal carcinoma and hepatocarcinoma. Other cancers include Acute Lymphoblastic Leukemia; Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Acute Myeloid Leukemia; Adrenocortical Carcinoma Adrenocortical Carcinoma; AIDS-Related Cancers; AIDS-Related Lymphoma; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Basal Cell Carcinoma, see Skin Cancer (non-Melanoma); Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer; Bone Cancer, osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma; Brain Tumor; Brain Tumor, Brain Stem Glioma; Brain Tumor, Cerebellar Astrocytoma; Brain Tumor, Cerebral Astrocytoma/Malignant Glioma; Brain Tumor, Ependymoma; Brain Tumor, Medulloblastoma; Brain Tumor, Supratentorial Primitive Neuroectodermal Tumors; Brain Tumor, Visual Pathway and Hypothalamic Glioma; Brain Tumor; Breast Cancer; Breast Cancer and Pregnancy; Breast Cancer; Breast Cancer, Male; Bronchial Adenomas/Carcinoids; Burkitt's Lymphoma; Carcinoid Tumor; Carcinoid Tumor, Gastrointestinal; Carcinoma of Unknown Primary; Central Nervous System Lymphoma, Primary; Cerebellar Astrocytoma; Cerebral Astrocytoma/Malignant Glioma; Cervical Cancer; Childhood Cancers; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Myeloproliferative Disorders; Colon Cancer; Colorectal Cancer; Cutaneous T-Cell Lymphoma, see Mycosis Fungoides and Sezary Syndrome; Endometrial Cancer; Ependymoma; Esophageal Cancer; Esophageal Cancer; Ewing's Family of Tumors; Extracranial Germ Cell Tumor; Extragonadal Germ Cell Tumor; Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma; Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric (Stomach) Cancer; Gastric (Stomach) Cancer; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor; Glioma; Glioma, Childhood Brain Stem; Glioma, Childhood Cerebral Astrocytoma; Glioma, Childhood Visual Pathway and Hypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hematologic (Blood) Cancer, Hepatocellular (Liver) Cancer, Adult (Primary); Hepatocellular (Liver) Cancer, Childhood (Primary); Hodgkin's Lymphoma; Hodgkin's Lymphoma; Hodgkin's Lymphoma During Pregnancy; Hypopharyngeal Cancer; Hypothalamic and Visual Pathway Glioma; Intraocular Melanoma; Islet Cell Carcinoma (Endocrine Pancreas); Kaposi's Sarcoma; Kidney (Renal Cell) Cancer; Kidney Cancer; Laryngeal Cancer; Laryngeal Cancer; Leukemia, Acute Lymphoblastic; Leukemia, Acute Lymphoblastic; Leukemia, Acute Myeloid; Leukemia, Acute Myeloid; Leukemia, Chronic Lymphocytic; Leukemia; Chronic Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer, Adult (Primary); Liver Cancer, Childhood (Primary); Lung Cancer, Non-Small Cell; Lung Cancer, Small Cell; Lymphoma, AIDS-Related; Lymphoma, Burkitt's; Lymphoma, Cutaneous T-Cell, see Mycosis Fungoides and Sezary Syndrome; Lymphoma, Hodgkin's; Lymphoma, Hodgkin's; Lymphoma, Hodgkin's During Pregnancy; Lymphoma, Non-Hodgkin's; Lymphoma, Non-Hodgkin's; Lymphoma, Non-Hodgkin's During Pregnancy; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom's; Malignant Fibrous Histiocytoma of Bone/Osteosarcoma; Medulloblastoma; Melanoma; Melanoma, Intraocular (Eye); Merkel Cell Carcinoma; Mesothelioma, Adult Malignant; Mesothelioma; Metastatic Squamous Neck Cancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome; Multiple Myeloma/Plasma Cell Neoplasm' Mycosis Fungoides; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Adult Acute; Myeloid Leukemia, Childhood Acute; Myeloma, Multiple; Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Nasopharyngeal Cancer; Neuroblastoma; Non-Hodgkin's Lymphoma; Non-Hodgkin's Lymphoma; Non-Hodgkin's Lymphoma During Pregnancy; Non-Small Cell Lung Cancer; Oral Cancer; Oral Cavity Cancer, Lip and; Oropharyngeal Cancer; Osteosarcoma/Malignant Fibrous Histiocytoma of Bone; Ovarian Cancer; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Pancreatic Cancer; Islet Cell; Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer; Pheochromocytoma; Pineoblastoma and Supratentorial Primitive Neuroectodermal Tumors; Pituitary Tumor; Plasma Cell Neoplasm/Multiple Myeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer; Pregnancy and Hodgkin's Lymphoma; Pregnancy and Non-Hodgkin's Lymphoma; Primary Central Nervous System Lymphoma; Prostate Cancer; Rectal Cancer; Renal Cell (Kidney) Cancer; Renal Cell (Kidney) Cancer; Renal Pelvis and Ureter, Transitional Cell Cancer; Retinoblastoma; Rhabdomyosarcoma; Salivary Gland Cancer; Salivary Gland Cancer; Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma, Soft Tissue; Sarcoma, Soft Tissue; Sarcoma, Uterine; Sezary Syndrome; Skin Cancer (non-Melanoma); Skin Cancer; Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell Lung Cancer; Small Intestine Cancer; Soft Tissue Sarcoma; Soft Tissue Sarcoma; Squamous Cell Carcinoma, see Skin Cancer (non-Melanoma); Squamous Neck Cancer with Occult Primary, Metastatic; Stomach (Gastric) Cancer; Stomach (Gastric) Cancer; Supratentorial Primitive Neuroectodermal Tumors; T-Cell Lymphoma, Cutaneous, see Mycosis Fungoides and Sezary Syndrome; Testicular Cancer; Thymoma; Thymoma and Thymic Carcinoma; Thyroid Cancer; Thyroid Cancer; Transitional Cell Cancer of the Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational; Unknown Primary Site, Carcinoma of; Unknown Primary Site, Cancer of; Unusual Cancers of Childhood; Ureter and Renal Pelvis, Transitional Cell Cancer; Urethral Cancer; Uterine Cancer, Endometrial; Uterine Sarcoma; Vaginal Cancer; Visual Pathway and Hypothalamic Glioma; Vulvar Cancer; Waldenstrom's Macroglobulinemia; Wilms' Tumor; and Women's Cancers.

Neurologic diseases that may be treated include epilepsy, schizophrenia, bipolar disorder or other psychological and/or psychiatric disorders, neuropathies, skeletal muscle atrophy, and neurodegenerative diseases, e.g., a neurodegenerative disease. Exemplary neurodegenerative diseases include: Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), and Parkinson's disease. Another class of neurodegenerative diseases includes diseases caused at least in part by aggregation of poly-glutamine. Diseases of this class include: Huntington's Diseases, Spinalbulbar Muscular Atrophy (SBMA or Kennedy's Disease), Dentatorubropallidoluysian Atrophy (DRPLA), Spinocerebellar Ataxia 1 (SCAT), Spinocerebellar Ataxia 2 (SCA2), Machado-Joseph Disease (MJD; SCA3), Spinocerebellar Ataxia 6 (SCA6), Spinocerebellar Ataxia 7 (SCAT), and Spinocerebellar Ataxia 12 (SCA12).

Any other disease in which the Wnt pathway, TGFβ pathway, JAK/STAT pathway, the mTOR pathway, Pgp modulation, CK1, CK1γ, CK2, or PIMs plays a role may be treatable or preventable using compounds and methods described herein.

Dosage

As used herein, a “therapeutically effective amount” or “therapeutically effective dose” is an amount of a compound of the invention or a combination of two or more such compounds, which inhibits, totally or partially, the progression of the condition or alleviates, at least partially, one or more symptoms of the condition. A therapeutically effective amount can also be an amount which is prophylactically effective. The amount which is therapeutically effective will depend upon the patient's size and gender, the condition to be treated, the severity of the condition and the result sought. For a given patient, a therapeutically effective amount may be determined by methods known to those of skill in the art.

A therapeutically effective dose refers to that amount of the compound that results in amelioration of symptoms in a patient. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) and the ED₅₀ (effective dose for 50% maximal response). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between MTD and ED₅₀. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED₅₀ with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. In the treatment of crises, the administration of an acute bolus or an infusion approaching the MTD may be required to obtain a rapid response.

Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the CK1, CK1γ, CK2, Pim1-3, Wnt pathway, TGFβ pathway, JAK/STAT pathway, mTOR pathway, or Pgp modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. HPLC assays or bioassays can be used to determine plasma concentrations.

Dosage intervals can also be determined using the MEC value. Compounds should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90% until the desired amelioration of symptoms is achieved. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

The amount of composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.

Kits

The compounds and compositions of the invention (e.g., compounds and compositions of formula I) may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labelled for treatment of an indicated condition. Instructions for use may also be provided.

EXEMPLIFICATION

The invention now being generally described, it will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention. The geometric isomers depicted below are believed to be correct, but final structural assignment will be made via 2-D NMR experiments. Although the exemplary compounds described below are believed to be the Z-geometric isomers, the E-geometric isomers and mixtures of the E- and Z-isomers are also contemplated by the present disclosure.

Example 1

(E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (1)

1,1-dimethoxy-N,N-dimethylmethanamine (100 g, 839 mmol, 1.02 equiv.) and 1,1-dimethoxypropan-2-one (97 g, 821 mmol) were added and stirred at 110° C. for 3 hours. The produced methanol was removed by a Dean-Stark apparatus. After the solution was cooled to room temperature, the remaining volatile materials were removed in vacuo to provide 130 g of the crude product, (E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (1) (130 g, 143 g theoretical, 91%). LC-MS m/z 283 (M+1). Reference: WO 2006/0097341A1, pg 67.

Example 2

Sodium 4-(dimethoxymethyl)pyrimidine-2-thiolate (2)

A solution of thiourea (64.7 g, 850 mmol, 1.13 equiv.), sodium methanolate (95%, 40.5 g, 751 mmol, 1.0 equiv.) in methanol (500 mL, 1.5 M) was stirred at room temperature for 30 minutes. A solution of (E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (1) (130 g, 751 mmol) in methanol (200 mL) was added and the reaction stirred at room temperature for 2 h. The crude sodium 4-(dimethoxymethyl)pyrimidine-2-thiolate (2) was used directly in the next step without further purification. LC-MS m/z 209 (M+1). Reference: WO 2006/0097341A1, pg 67.

Example 3

4-(dimethoxymethyl)-2-(methylthio)pyrimidine (3)

Iodomethane (128 g, 902 mmol, 1.20 equiv.) was added carefully to the crude solution of sodium 4-(dimethoxymethyl)pyrimidine-2-thiolate (2) (156 g, 751 mmol) in methanol (700 mL, 1.1 M) while maintaining the reaction temperature below 28° C. using an ice-water bath for cooling. The resulting mixture was stirred at room temperature for 16 h. After removal of the solvent under reduced pressure, the residue was diluted with water (300 mL) and extracted with ethyl acetate (2×150 mL). The combined organic layer was concentrated under reduced pressure and the crude residue purified by passing through a short silica gel pad and washing with diethyl ether (200 mL) to afford 4-(dimethoxymethyl)-2-(methylthio)pyrimidine (3) as a brown oil (53.7 g, 150 g theoretical, 35.7%). LC-MS m/z 201 (M+1). Reference: WO 2006/0097341A1, pg 67.

Example 4

2-(methylthio)pyrimidine-4-carbaldehyde (4): 4-(dimethoxymethyl)-2-(methylthio)pyrimidine (3) (53.7 g, 268 mmol) was added carefully to 1.2 N aqueous HCl (300 mL, 268 mmol, 1.0 equiv.) and stirred at 60° C. for 3 hours. The reaction mixture was then cooled to room temperature and neutralized by the slow addition of solid sodium bicarbonate. The crude mixture was extracted with diethyl ether (3×150 mL) and the combined organic layer was concentrated under reduced pressure to afford 2-(methylthio)pyrimidine-4-carbaldehyde (4) as a yellow solid (14.2 g, 41.5 g theoretical, 34%). LC-MS m/z 155 (M+1). Reference: WO 2006/009734 A1, pg 67.

Example 5

(Z)-5-((2-(methylthio)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (5)

A 40 mL round-bottomed vial was charged with 2-(methylthio)pyrimidine-4-carbaldehyde (4) (771 mg, 5 mmol), thiazolidine-2,4-dione (586 mg, 5 mmol, 1.0 equiv.), and piperidine (400 μL, 4 mmol, 0.8 equiv.) in ethanol (20 mL, 0.25 M). The reaction mixture was heated to 80° C. and shaken for 20 h. The resulting yellow precipitate was isolated by filtration and washed with ethanol (1×20 mL) and dried in vacuo to afford (Z)-5-((2-(methylthio)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (5) as a yellow solid (550 mg, 898 mg theoretical, 61%). LC-MS m/z 254 (M+1).

Example 6

(Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (6)

A mixture of (Z)-5-((2-(methylthio)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (5) (3.5 g, 13.82 mmol) in THF (100 mL, 0.13 M) was treated with a solution of oxone (25.8 g, 41.5 mmol, 3.0 equiv.) in water (175 mL). The resulting mixture was stirred at room temperature for 48 h. The resulting precipitate was filtered and washed with water (20 mL) and diethyl ether (20 mL) to afford (Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (6) as a solid (2.48 g, 3.94 g theoretical, 63%). LC-MS m/z 286 (M+1).

Example 7

General Displacement Procedure 1:

2 dram round bottomed vials were charged with (Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (6) (25 mg, 0.0877 mmol), DMSO (1 mL, 0.08 M), diisopropylethylamine (50 μL, 0.288 mmol, 3.2 equiv.), and the appropriate amine (0.0877 mmol, 1.0 equiv.). The reaction mixture was heated to 120° C. and shaken for 16 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4).

Example 8

(Z)-5-((2-(4-(benzo[d][1,3]dioxol-5-ylmethyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-(benzo[d][1,3]dioxol-5-ylmethyl)piperazine (16.6 mg, 37.4 mg theoretical, 44.3%). LC-MS m/z 426.5 (M+1).

Example 9

(Z)-5-((2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-(p-tolyl)piperazine (12.5 mg, 33.6 mg theoretical, 37.2%). LC-MS m/z 382.5 (M+1).

Example 10

(Z)-5-((2-(methyl(2-(pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and N-methyl-2-(pyridin-2-yl)ethanamine (13.7 mg, 30 mg theoretical, 45.6%). LC-MS m/z 342.4 (M+1).

Example 11

(Z)-5-((2-(4-isopropylpiperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-isopropylpiperazine (15.3 mg, 29.3 mg theoretical, 52.1%). LC-MS m/z 334.4 (M+1).

Example 12

(Z)-5-((2-(3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1,2,3,4-tetrahydroisoquinoline (0.1 mg, 29.8 mg theoretical, 0.3%). LC-MS m/z 339.4 (M+1).

Example 13

(Z)-5-((2-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-(pyridin-2-yl)piperazine (25.7 mg, 32.4 mg theoretical, 79.3%). LC-MS m/z 369.4 (M+1).

Example 14

(Z)-methyl 1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)pyrrolidine-2-carboxylate was prepared using the general displacement procedure and methylpyrrolidine-2-carboxylate (3.1 mg, 29.4 mg theoretical, 10.5%). LC-MS m/z 335.4 (M+1).

Example 15

(Z)-5-((2-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-methylpiperazine (0.1 mg, 26.9 mg theoretical, 0.4%). LC-MS m/z 306.4 (M+1).

Example 16

(Z)-5-((2-(4-morpholinopiperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 4-(piperidin-4-yl)morpholine (14.7 mg, 33 mg theoretical, 44.5%). LC-MS m/z 376.4 (M+1).

Example 17

(Z)-tert-butyl (1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)pyrrolidin-3-yl)carbamate was prepared using the general displacement procedure and tert-butyl pyrrolidin-3-ylcarbamate (0.1 mg, 34.4 mg theoretical, 0.3%). LC-MS m/z 392.4 (M+1).

Example 18

(Z)-5-((2-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 2-(piperazin-1-yl)pyrimidine (3.1 mg, 32.5 mg theoretical, 9.5%). LC-MS m/z 370.4 (M+1).

Example 19

(Z)-5-((2-morpholinopyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and morpholine (7.8 mg, 25.7 mg theoretical, 30.3%). LC-MS m/z 293.3 (M+1).

Example 20

(Z)-5-((2-(piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and piperidine (8.9 mg, 25.5 mg theoretical, 34.8%). LC-MS m/z 291.3 (M+1).

Example 21

(Z)-5-((2-(pyrrolidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and pyrrolidine (8.3 mg, 24.3 mg theoretical, 34.1%). LC-MS m/z 277.3 (M+1).

Example 22

(Z)-5-((2-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 4-(pyrrolidin-1-yl)piperidine (9.3 mg, 31.6 mg theoretical, 29.4%). LC-MS m/z 360.4 (M+1).

Example 23

(Z)-tert-butyl 4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperazine-1-carboxylate was prepared using the general displacement procedure and tert-butyl piperazine-1-carboxylate (6.7 mg, 34.4 mg theoretical, 19.5%). LC-MS m/z 392.4 (M+1).

Example 24

(Z)-tert-butyl 4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)-1,4-diazepane-1-carboxylate was prepared using the general displacement procedure and tert-butyl 1,4-diazepane-1-carboxylate (5.1 mg, 35.7 mg theoretical, 14.3%). LC-MS m/z 406.5 (M+1).

Example 25

(Z)-5-((2-(4-(2-morpholino-2-oxoethyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-morpholino-2-(piperazin-1-yl)ethanone (11.4 mg, 36.8 mg theoretical, 31%). LC-MS m/z 419.5 (M+1).

Example 26

(Z)-5-((2-(4-phenylpiperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-phenylpiperazine (11.3 mg, 32.3 mg theoretical, 35%). LC-MS m/z 368.4 (M+1).

Example 27

(Z)-5-((2-(methyl(phenethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and N-methyl-2-phenylethanamine (8.3 mg, 30 mg theoretical, 27.7%). LC-MS m/z 341.4 (M+1).

Example 28

(Z)-5-((2-(4-(pyridin-4-yl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-(pyridin-4-yl)piperazine (7 mg, 32.4 mg theoretical, 21.6%). LC-MS m/z 369.4 (M+1).

Example 29

(Z)-tert-butyl (1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)carbamate was prepared using the general displacement procedure and tert-butyl piperidin-4-ylcarbamate (5.9 mg, 35.7 mg theoretical, 16.5%). LC-MS m/z 406.5 (M+1).

Example 30

(Z)-tert-butyl ((1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-3-yl)methyl)carbamate was prepared using the general displacement procedure and tert-butyl (piperidin-3-ylmethyl)carbamate (0.1 mg, 36.9 mg theoretical, 0.3%). LC-MS m/z 420.5 (M+1).

Example 31

(Z)-5-((2-(4-aminopiperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and tert-butyl piperidin-4-ylcarbamate. The purified boc-protected was then treated with dichloromethane (1.0 mL), hydrochloric acid in methanol (500 μL, 1.25 M)) and shaken at 50° C. for 16 h. The reaction mixture was then concentrated under reduced pressure (Genevac HT-4) to provide (1.7 mg, 26.9 mg theoretical, 6.3%). LC-MS m/z 306.4 (M+1).

Example 32

General Displacement Procedure 2:

2 dram round-bottomed vials were charged with (Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (25 mg, 0.0877 mmol), DMSO (1 mL, 0.08 M), diisopropylethylamine (50 μL, 0.288 mmol, 3.2 equiv.), and the appropriate amine (0.0877 mmol, 1.0 equiv.). The reaction mixture was heated to 110° C. and shaken for 24 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4).

Example 33

(Z)-5-((2-(4-benzoylpiperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and phenyl(piperazin-1-yl)methanone (4.1 mg, 34.7 mg theoretical, 11.8%). LC-MS m/z 396 (M+1).

Example 34

(R,Z)-5-((2-(4-benzyl-3-(hydroxymethyl)-5-oxopiperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and (R)-1-benzyl-6-(hydroxymethyl)piperazin-2-one (5.1 mg, 37.4 mg theoretical, 13.6%). LC-MS m/z 426 (M+1).

Example 35

(Z)—N-(1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)pyrrolidin-3-yl)-N-ethylacetamide was prepared using the general displacement procedure and N-ethyl-N-(pyrrolidin-3-yl)acetamide (12.1 mg, 31.8 mg theoretical, 38%). LC-MS m/z 362 (M+1).

Example 36

(Z)-5-((2-(3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and N,N-dimethylpyrrolidin-3-amine (12.2 mg, 28.1 mg theoretical, 43.4%). LC-MS m/z 320 (M+1).

Example 37

(Z)-5-((2-(methyl(1-methylpyrrolidin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and N,1-dimethylpyrrolidin-3-amine (1.1 mg, 28.1 mg theoretical, 3.9%). LC-MS m/z 320 (M+1).

Example 38

(Z)-5-((2-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 2-(piperazin-1-yl)ethanol (4.4 mg, 29.5 mg theoretical, 14.9%). LC-MS m/z 336 (M+1).

Example 39

(Z)-5-((2-(4-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 2-(piperazin-1-yl)-4-(trifluoromethyl)pyrimidine (5.8 mg, 38.5 mg theoretical, 15.1%). LC-MS m/z 438 (M+1).

Example 40

(Z)-5-((2-(4-(4-(benzyloxy)phenyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-(4-(benzyloxy)phenyl)piperazine (4 mg, 41.7 mg theoretical, 9.6%). LC-MS m/z 474 (M+1).

Example 41

(Z)-5-((2-(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-(4-chloro-2-fluorophenyl)piperazine (4.8 mg, 36.9 mg theoretical, 13%). LC-MS m/z 420 (M+1).

Example 42

(Z)-5-((2-(4-(4-(tert-butyl)phenyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-(4-(tert-butyl)phenyl)piperazine (3.7 mg, 37.2 mg theoretical, 10%). LC-MS m/z 424 (M+1).

Example 43

(Z)-5-((2-(4-(3,5-bis(trifluoromethyl)phenyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-(3,5-bis(trifluoromethyl)phenyl)piperazine (3.8 mg, 44.3 mg theoretical, 8.6%). LC-MS m/z 504 (M+1).

Example 44

(Z)-5-((2-(4-(4-(trifluoromethyl)pyrimidin-2-yl)-1,4-diazepan-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-(4-(trifluoromethyl)pyrimidin-2-yl)-1,4-diazepane (4.9 mg, 39.7 mg theoretical, 12.3%). LC-MS m/z 452 (M+1).

Example 45

(Z)-5-((2-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-([1,1′-biphenyl]-4-yl)piperazine (1.2 mg, 39 mg theoretical, 3.1%). LC-MS m/z 444 (M+1).

Example 46

(Z)-5-((2-(4-(furan-2-carbonyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and furan-2-yl(piperazin-1-yl)methanone (6 mg, 33.9 mg theoretical, 17.7%). LC-MS m/z 386 (M+1).

Example 47

(Z)-5-((2-(4-((4-fluorophenyl)(phenyl)methyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-((4-fluorophenyl)(phenyl)methyl)piperazine (14.4 mg, 41.8 mg theoretical, 34.4%). LC-MS m/z 476 (M+1).

Example 48

(Z)-5-((2-(4-(naphthalen-1-yl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-(naphthalen-1-yl)piperazine (6.2 mg, 36.7 mg theoretical, 16.9%). LC-MS m/z 418 (M+1).

Example 49

(Z)-5-((2-(4-([1,1′-biphenyl]-3-yl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-([1,1′-biphenyl]-3-yl)piperazine (10.4 mg, 39 mg theoretical, 26.7%). LC-MS m/z 444 (M+1).

Example 50

(Z)-5-((2-(4-((4-fluorophenyl)sulfonyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-((4-fluorophenyl)sulfonyl)piperazine (5.2 mg, 39.6 mg theoretical, 13.1%). LC-MS m/z 450 (M+1).

Example 51

(Z)-1-tert-butyl 2-methyl 4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperazine-1,2-dicarboxylate was prepared using the general displacement procedure and 1-tert-butyl 2-methyl piperazine-1,2-dicarboxylate (2.8 mg, 39.6 mg theoretical, 7%). LC-MS m/z 450 (M+1).

Example 52

(Z)-5-((2-(4-benzyl-3-(hydroxymethyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and (1-benzylpiperazin-2-yl)methanol (1.7 mg, 36.2 mg theoretical, 4.7%). LC-MS m/z 413 (M+1).

Example 53

(Z)-5-((2-(5-oxo-1,4-diazepan-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1,4-diazepan-5-one (1.1 mg, 28.1 mg theoretical, 3.9%). LC-MS m/z 320 (M+1).

Example 54

(Z)-5-((2-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-(4-(trifluoromethyl)phenyl)piperazine (3.3 mg, 38.3 mg theoretical, 8.6%). LC-MS m/z 436 (M+1).

Example 55

(Z)-5-((2-(4-cyclohexylpiperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-cyclohexylpiperazine (10.7 mg, 32.9 mg theoretical, 32.5%). LC-MS m/z 374 (M+1).

Example 56

(Z)-5-((2-(methyl(3-(piperidin-1-yl)propyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and N-methyl-3-(piperidin-1-yl)propan-1-amine (10.2 mg, 31.8 mg theoretical, 32.1%). LC-MS m/z 362 (M+1).

Example 57

(Z)-5-((2-(4-((1-methylpiperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-((1-methylpiperidin-4-yl)methyl)piperazine (7.3 mg, 42.3 mg theoretical, 17.2%). LC-MS m/z 403 (M+1).

Example 58

(Z)-1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)piperidine-4-carboxamide was prepared using the general displacement procedure and N-(2-hydroxyethyl)piperidine-4-carboxamide (10.8 mg, 39.7 mg theoretical, 27.2%). LC-MS m/z 378 (M+1).

Example 59

(Z)-5-((2-(4-(4-methylpiperazine-1-carbonyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and (4-methylpiperazin-1-yl)(piperidin-4-yl)methanone (5.5 mg, 43.8 mg theoretical, 12.6%). LC-MS m/z 417 (M+1).

Example 60

(Z)-5-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-methyl-4-(piperidin-4-yl)piperazine (12.4 mg, 40.9 mg theoretical, 30.4%). LC-MS m/z 389 (M+1).

Example 61

(Z)-5-((2-(4-(dimethylamino)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and N,N-dimethylpiperidin-4-amine (5 mg, 35.1 mg theoretical, 14.3%). LC-MS m/z 334 (M+1).

Example 62

(Z)-1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidine-4-carbonitrile was prepared using the general displacement procedure and piperidine-4-carbonitrile (7.5 mg, 33.2 mg theoretical, 22.6%). LC-MS m/z 316 (M+1).

Example 63

(Z)-5-((2-((2-hydroxy-2-phenylethyl)(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 2-(methylamino)-1-phenylethanol (10.8 mg, 37.5 mg theoretical, 28.8%). LC-MS m/z 357 (M+1).

Example 64

General Displacement Procedure 3:

2 dram round-bottomed vials were charged with (Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (50 mg, 0.175 mmol), DMSO (2 mL, 0.08 M), diisopropylethylamine (34 μL, 0.193 mmol, 1.1 equiv.), and the appropriate amine (0.175 mmol, 1.0 equiv.). The reaction mixture was heated to 100° C. and shaken for 24 h. The solvent was removed under reduced pressure (Genevac HT-4). The crude was then charged with 2 mL DCE and 500 μL of TFA and shaken for 24 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4).

Example 65

(Z)-5-((2-(4-(aminomethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and tert-butyl (piperidin-4-ylmethyl)carbamate (49 mg, 55.9 mg theoretical, 88%). LC-MS m/z 320 (M+1).

Example 66

(Z)-5-((2-(methyl(piperidin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and tert-butyl 3-(methylamino)piperidine-1-carboxylate (2.3 mg, 55.9 mg theoretical, 4.1%). LC-MS m/z 320 (M+1).

Example 67

(Z)-5-((2-(3-methylpiperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and tert-butyl 2-methylpiperazine-1-carboxylate (1.5 mg, 53.4 mg theoretical, 2.8%). LC-MS m/z 306 (M+1).

Example 68

(Z)-5-((2-(piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and tert-butyl piperazine-1-carboxylate (17.7 mg, 51 mg theoretical, 34.7%). LC-MS m/z 292 (M+1).

Example 69

(Z)-5-((2-(1,4-diazepan-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and tert-butyl 1,4-diazepane-1-carboxylate (15.2 mg, 53.4 mg theoretical, 28.4%). LC-MS m/z 306 (M+1).

Example 70

(Z)-5-((2-(3-aminopyrrolidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and tert-butyl pyrrolidin-3-ylcarbamate (16.5 mg, 51 mg theoretical, 32.4%). LC-MS m/z 292 (M+1).

Example 71

(Z)-5-((2-(3-aminopiperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and tert-butyl piperidin-3-ylcarbamate (16.9 mg, 29.8 mg theoretical, 53.4%). LC-MS m/z 306 (M+1).

Example 72 Synthesis of (Z)-5-((6-(2-methoxyethoxy)-2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione

A 25 mL round-bottomed flask was charged with 2-methoxyethanol (57 μL, 1 equiv.) and THF (2.5 mL). 60% NaH in oil (21 mg, 1.1 equiv.) was added at 0° C. under argon. The reaction mixture was stirred for 5 min at −5° C. and for 1 h 15 min at RT. Methyl 2,6-dichloropyrimidine-4-carboxylate (150 mg, 1 equiv.) dissolved in THF (1 mL) was added over 5 min at −78° C. The reaction mixture was stirred for 4 h warming from −78° C. to 0° C. LC-MS after 3 h (−15° C.) showed 2 peaks (2:1 ratio) with the desired mass at 1.57 min and 1.67 min (M+1=247 & 249). The reaction mixture was quenched with 10% NH₄Cl (5 mL) at 0° C. The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layer was dried over Na₂SO₄ and concentrated under reduced pressure to provide 161 mg of a crude mixture of methyl 2-chloro-6-(2-methoxyethoxy)pyrimidine-4-carboxylate and methyl 6-chloro-2-(2-methoxyethoxy)pyrimidine-4-carboxylate which was partially separated by flash chromatography on silica gel (10 g, Hexanes/EtOAc 9:1 to 7:3).

F1: 47 mg pure desired isomer 6-alkoxy (26%, 179 mg theoretical)

F2: 19.3 mg mixture of isomers (11%)

F3: 28.8 mg pure undesired isomer 2-alkoxy (16%)

A 25 mL round bottomed flask was charged with methyl 2-chloro-6-(2-methoxyethoxy)pyrimidine-4-carboxylate [SAD105-047F1] (45 mg, 1 equiv.) and CH₂Cl₂ (1 mL). 1 M DIBAL-H (0.2 mL, 1.1 equiv.) was added at −78° C. over 2 min under argon. The reaction mixture was stirred for 3 h at −78° C. but the LC-MS still showed a lot of starting material. Additional 1 M DIBAL-H (0.27 mL, 1.4 equiv.) was added at −78° C. over 2 min under argon and after 0.5 h LC-MS showed no more starting material but mostly 1 peak at 1.20 min (M+1=217, M+1+MeOH=249). The reaction mixture was quenched with MeOH (0.5 mL) and then with 10% NH₄Cl (1 mL). The reaction mixture was warmed to RT and then the solvent was concentrated under reduced pressure. The residue was diluted with 10% NH₄Cl (4 mL). The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layer was dried over Na₂SO₄ and concentrated under reduced pressure to provide 41.9 mg of the crude 2-chloro-6-(2-methoxyethoxy)pyrimidine-4-carbaldehyde as a yellow oil which was used in the next step without further purification, (H NMR δ: 9.91 (s, 1H); 7.23 (s, 1H); 4.59-4.64 (m, 2H), 3.7-3.8 (m, 2H); 3.44 (s, 3H).

Crude 2-chloro-6-(2-methoxyethoxy)pyrimidine-4-carbaldehyde (sad105-052, 41.9 mg) was dissolved in ethanol (1.5 mL) and was added to a 10 mL vial containing the thiazolidine-dione (21.3 mg, 0.18 mmol) and the 1-(p-tolyl)piperazine (39.3 mg, 0.18 mmol). The reaction mixture was shaken at 80° C. for 15.5 h. LC-MS showed a peak with the desired mass at 2.18 min (M+1=456). The solvent was concentrated under reduced pressure and the residue was dissolved in EtOAc (20 mL) and washed with saturated NaHCO₃ (10 mL). The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure to provide 85.7 mg of brown oil. Purification by flash chromatography (SiO₂, 10 g, Hexanes/EtOAc 9:1 to 6:4 to 1:1) provided 11.5 mg (13.9% 2 steps, 83 mg theoretical) of pure (Z)-5-((6-(2-methoxyethoxy)-2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione as a yellow solid.

Example 73 Synthesis of (Z)-5-((6-methoxy-2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione

A 40 mL round-bottomed vial was charged with methanol (120 μL of 200 μL MeOH in 1 mL Acetonitrile, 1 equiv.), K₂CO₃ (67 mg, 1 equiv.), methyl 2,6-dichloropyrimidine-4-carboxylate (100 mg, 1 equiv.), and acetonitrile (2 mL). The reaction mixture was shaken for 2.5 h at RT but LC-MS showed only starting material. The reaction mixture was then shaken for 1 h at 85° C. LC-MS showed the formation of a small amount of desired product (1.51 min, M+1=203). Methanol (0.200 mL, 10 equiv.) was added and the reaction mixture was shaken for 15 h at 85° C. LC-MS showed mostly 1 peak in the UV and MS at 1.53 min and a tiny amount of bis-methoxypyrimidine. The solid precipitate was filtered off and the filtrate was evaporated to give 89 mg (91% crude yield, theoretical 98 mg) of crude desired product. H NMR showed an 11:1 mixture of desired product and bis-methoxypyrimidine side product (M+1=199). The material was used in the next step without further purification.

A 25 mL round-bottomed flask was charged with methyl 2-chloro-6-methoxypyrimidine-4-carboxylate [sad105-055 crude] (74 mg, 1 equiv.) under argon. 1M DIBAL-H in dichloromethane (0.73 mL, 2 equiv.) was added over 5 min and the reaction mixture was stirred at −78° C. for 45 min. After 0.5 h, LC-MS showed the reaction was complete. The reaction was quenched at −78° C. with methanol (0.5 mL) and then with 10% NH₄Cl (2 mL). The solvents were concentrated under reduced pressure and the residue was diluted with 10% NH₄Cl (3 mL). The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layer was dried over Na₂SO₄ and concentrated under reduced pressure to provide the crude product 2-chloro-6-methoxypyrimidine-4-carbaldehyde as an orange oil (76 mg, 63 mg theoretical, 121%). LC-MS m/z: 205.0: (M+1+MeOH, hemiacetal with methanol). Some over-reduced alcohol was also observed in the crude (2.17 min, M+1=175). The crude aldehyde was used directly in the next step without further purification.

Crude 2-chloro-6-methoxypyrimidine-4-carbaldehyde (sad105-058, 76 mg) was dissolved in ethanol (2 mL) and was added to a 10 mL vial containing the thiazolidine-dione (42.8 mg, 0.37 mmol., 1 equiv.) and the 1-(p-tolyl)piperazine (70.8 mg, 0.40 mmol, 1.1 equiv.). The mixture was shaken for 45 h at 80° C. and for 15 h at 90° C. producing a precipitate. LC-MS of the solution showed some product at (M+1=412) and some intermediate at (M+1=430). The desired product crashed out of the solution and the LC-MS of the solution does not reflect well the conversion of the reaction. The yellow solid was filtered using a Pasteur pipette through a pad of glass wool and the solid was rinsed with EtOH (4×0.5 mL). The ethanol filtrate contains some desired product. The solid was re-dissolved in CH₂Cl₂ and the insoluble solid was filtered off. The filtrate was concentrated under reduced pressure to provide 20 mg of the desired product (Z)-5-((6-methoxy-2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (97.3% pure). The insoluble solid was partitioned between saturated NaHCO₃ (3 mL) and CH₂Cl₂ (2×5 mL). The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure to provide an additional 13.4 mg of the desired product (total 33.4 mg, 150 mg theoretical, 22%). LC-MS m/z: 412 (M+1).

Example 74 Synthesis of (Z)-5-((2-(4-(p-tolyl)piperazin-1-yl)pyridin-4-yl)methylene)thiazolidine-2,4-dione

A 40 mL round-bottomed vial was charged with methyl 2-chloroisonicotinate (200 mg, 1.17 mmol, 1 equiv.) and 1-(p-tolyl)piperazine (205 mg, 1.17 mmol, 1 equiv.). Toluene (3 mL) and DMSO (3 mL) were added followed by potassium carbonate (403 mg, 2.9 mmol, 2.5 equiv.). The mixture was shaken for 18 h at 100° C. LC-MS after 18 h showed a peak at 1.68 min with the desired mass (M+1=312) with the chloropyridine starting material co-eluting (M+1=172). The reaction mixture was diluted with water (5 mL) and the aqueous layer was extracted with CH₂Cl₂ (3×10 mL). The combined organic layer was dried over Na₂SO₄ and then concentrated under reduced pressure. The crude mixture was purified on silica gel (10 g, Hexanes/EtOAc 9:1 to 1:1) to provide the desired product as white crystals (27 mg, 67 mg theoretical, 40%).

A 25 mL round-bottomed flask was charged with methyl 2-(4-(p-tolyl)piperazin-1-yl)isonicotinate (27 mg, 0.087 mmol, 1 equiv.) and CH₂Cl₂ (1 mL). 1 M DIBAL-H in CH₂Cl₂ (130 μL, 0.13 mmol, 1.5 equiv.) was added under argon at −78° C. over 2 min. The reaction mixture was quenched with MeOH (0.5 mL) at −78° C. The LC-MS of the crude mixture showed a 1:1 mixture of the alcohol (1.21 min, M+1=284) and the aldehyde as a hemiacetal with methanol (1.38 min, M+1+MeOH=314.3). The crude aldehyde was used directly in the next step without any further purification.

Crude 2-(4-(p-tolyl)piperazin-1-yl)isonicotinaldehyde [sad105-080] was dissolved in ethanol (1 mL) and was added to a 10 mL vial containing the thiazolidine-dione (10.2 mg, 0.087 mmol) and the 1-(p-tolyl)piperazine (5.9 mg, 0.087 mmol). The reaction mixture was shaken at 90° C. for 19.5 h. LC-MS showed a new peak with the desired mass at 1.78 min (M+1=381). The reaction was concentrated under reduced pressure and the residue was purified by flash chromatography (SiO₂, 10 g, Hexanes/EtOAc 9:1 to 4:6) to provide 10.1 mg (30% over two steps, 33.1 mg theoretical) of (Z)-5-(2-(4-(p-tolyl)piperazin-1-yl)pyridin-4-yl)methylene)thiazolidine-2,4-dione as a yellow solid. The yellow solid was dissolved in hot EtOH (0.5 mL). On cooling a yellow solid precipitated, which was filtered through a pad of glass wool and washed with 0.25 mL ethanol. The solid was re-dissolved in CH₂Cl₂ and was concentrated under reduced pressure to provide 1.7 mg of the title product. LC-MS m/z: (M+1=381).

Example 75 Synthesis of (Z)-5-((6-(4-(p-tolyl)piperazin-1-yl)pyridin-2-yl)methylene)thiazolidine-2,4-dione

A 40 mL round-bottomed vial was charged with thiazolidine-2,4-dione (300 mg, 2.56 mmol, 1 equiv.) and 6-bromopicolinaldehyde (477 mg, 2.56 mmol, 1 equiv.). Toluene (5 mL, 0.5 M), glacial acetic acid (22 μL, 0.38 mmol, 0.15 equiv.), and piperidine (25 μL, 0.25 mmol, 0.1 equiv.) were added and the vial was purged with argon. The mixture was shaken for 16 h at 125° C. The resulting solid was collected by filtration and then washed with acetone (3×5 mL). The solid was dried under reduced pressure to provide (Z)-5-((6-bromopyridin-2-yl)methylene)thiazolidine-2,4-dione (439 mg, 731 mg theoretical, 60%). LC-MS m/z: 286 (M+1).

An 8 mL round bottomed vial was charged with 1-(p-tolyl)piperazine (56 mg, 0.318 mmol, 1 equiv.) and DMSO (1 mL, 0.3 M), DiPEA (105 μL, 0.636 mmol, 2 equiv.), (Z)-5-((6-bromopyridin-2-yl)methylene)thiazolidine-2,4-dione (91 mg, 0.318 mmol, 1 equiv.), and the vial was purged with argon. The mixture was shaken for 48 h at 110° C. The reaction mixture was then partitioned between CH₂Cl₂ (10 mL) and sat. NaCl (20 mL). The aqueous layer was back extracted with CH₂Cl₂ (2×15 mL) and the combined organic layer was dried over xxx and concentrated under reduced pressure to provide an orange residue. The orange residue was triturated with ether (3×15 mL) to provide (Z)-5-((6-(4-(p-tolyl)piperazin-1-yl)pyridin-2-yl)methylene)thiazolidine-2,4-dione as an orange solid (65 mg, 122 mg theoretical, 53%). LC-MS m/z: 382 (M+1).

Example 76

(Z)-5-((6-(methyl(phenethyl)amino)pyridin-2-yl)methylene)thiazolidine-2,4-dione

An 8 mL round-bottomed vial was charged with N-methyl-2-phenylethanamine (43 mg, 0.318 mmol, 1 equiv.) and DMSO (1 mL, 0.3 M), DiPEA (105 μL, 0.636 mmol, 2 equiv.), (Z)-5-((6-bromopyridin-2-yl)methylene)thiazolidine-2,4-dione (91 mg, 0.318 mmol, 1 equiv.), and the vial was purged with argon. The mixture was shaken for 48 h at 110° C. The reaction mixture was then partitioned between CH₂Cl₂ (10 mL) and sat. NaCl (20 mL). The aqueous layer was back extracted with CH₂Cl₂ (2×15 mL) and the combined organic layer was dried over xxx and concentrated under reduced pressure to provide an orange residue. The orange residue was triturated with ether (3×15 mL) to provide (Z)-5-((6-(methyl(phenethyl)amino)pyridin-2-yl)methylene)thiazolidine-2,4-dione as an orange film (2.6 mg, 175 mg theoretical, 5%). LC-MS m/z: 340 (M+1).

Example 77 General Procedure 1 for the Preparation of Amino-Analogs

Methyl 2,6-dichloropyrimidine-4-carboxylate (200 mg, 0.966 mmol) in 2 mL of THF was treated with DIPEA (185 μL, 1.06 mmol) and the reaction was then cooled to 0° C. A solution of the appropriate amine (1 equiv., 0.966 mmol) in 2 mL of THF was then added slowly to the reaction mixture. The reaction mixture was shaken for 2 h and then concentrated under reduced pressure to provide a light yellow crude product, which was used without any further purification.

The light yellow crude product (1 equiv.) was treated with DCM (2 mL). The reaction mixture was then cooled to −70° C. and treated dropwise with 1 M DIBALH (180 μL, 1.1 equiv.) and stirred for 2 h. Another 100 μL of DIBALH was added dropwise and stirred for an additional 3 h. MeOH (1 mL) was then added to quench the reaction. The reaction mixture was then allowed to warm to room temperature and partitioned between water (5 mL) and DCM (5 mL). The DCM layer was collected and concentrated under reduced pressure. Flash chromatography using 50%-80% EtOAc/Hexanes provided the desired aldehyde.

The aldehyde was treated with thiazolidine-2,4-dione (1 equiv.) and 1-(p-tolyl)piperazine (1.1 equiv.) in 2 ml, of EtOH. The reaction mixture was then heated to 85° C. for 16 h and then further heated to 95° C. for 24 h. The reaction mixture was then concentrated and purified by Biotage chromatography using 1:1 hexanes/EtOAc to provide the final amino-analogs.

Example 78

(Z)-5-((6-(methyl(phenethyl)amino)-2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using General Procedure 1 for the Preparation of Amino-Analogs and N-methyl-2-phenylethanamine (4.2 mg, 90 mg theoretical, 5%, 3 steps). LC-MS m/z: 515 (M+1).

Example 79

(Z)-5-((6-(benzyl(methyl)amino)-2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using General Procedure 1 for the Preparation of Amino-Analogs and N-methylbenzylamine (5.1 mg, 85 mg theoretical, 6%, 3 steps). LC-MS m/z: 501 (M+1).

Example 80

(Z)-5-((6-((2-methoxyethyl)(methyl)amino)-2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and N-methyl-1-phenylmethanamine (34 mg, 142 mg theoretical, 23.9%, 3 steps). LC-MS m/z 501: (M+1).

Example 81 General Procedure 2 for the Preparation of Amino-Analogs

Methyl 2,6-dichloropyrimidine-4-carboxylate (200 mg, 0.966 mmol) in 2 mL of THF was treated with DIPEA (185 μL, 1.06 mmol) and then cooled to 0° C. A solution of the appropriate amine (1 equiv., 0.966 mmol) in 2 mL of THF was then added slowly. The reaction mixture was shaken for 2 h and concentrated under reduced pressure to provide a light yellow crude product, which was used without any further purification.

The crude material was treated with 2 mL of EtOH, DIPEA (1.1 equiv.), and 1-(p-tolyl)piperazine (1 equiv.). The reaction mixture was then heated to 90° C. for 2 d. LCMS showed the desired product along with the EtO version of the ester. The reaction mixture was then concentrated under reduced pressure and purified using a Biotage with 10-100% EtOAc/Hexanes to provide the desired di-aminoester intermediate.

The di-aminoester intermediate was treated with DCM (2 mL) and cooled to −10° C. DIBALH (3 equiv.) was added dropwise and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. Methanol (1 mL) was added to quench the reaction and then allowed to stir for 30 min. The reaction mixture was then partitioned between DCM (10 mL) and H₂O (10 mL). The aqueous layer was back extracted with DCM (2×10 mL) and the combined organic layer was concentrated under reduced pressure. The crude residue was purified on silica gel using 5-10% MeOH/DCM to provide the desired alcohol.

The alcohol (1 equiv.) was treated with 2 mL of DCM and the reaction mixture was cooled to 0° C. and treated with 1.4 mL of 15% Dess Martin reagent in DCM. The reaction mixture was stirred for 1 h and treated with an additional portion of Dess Martin reagent (1.1 equiv.) at 0° C., and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was then concentrated under reduced pressure and the crude residue was purified by flash chromatography using 5-10% MeOH/DCM to provide the desired aldehyde.

The aldehyde was treated with thiazolidine-2,4-dione (1 equiv.), piperidine (0.8 equiv.), and 2 mL of EtOH. The reaction mixture was then heated to 85° C. for 16 h and then concentrated under reduced pressure. The residue was then triturated with DCM (2 mL), MeOH (2 mL), and EtOAc (2 mL) to provide the final amino-analogs.

Example 82

(Z)-5-((6-(methyl(2-(pyridin-2-yl)ethyl)amino)-2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and N-methyl-2-(pyridin-2-yl)ethanamine (12.7 mg, 160 mg theoretical, 1.7%, 5 steps). LC-MS m/z: 516 (M+1).

Example 83

(Z)-5-((6-((2-methoxyethyl)(methyl)amino)-2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 2-methoxy-N-methylethanamine (34 mg, 680 mg theoretical, 5%, 5 steps). LC-MS m/z: 469 (M+1).

Example 84

(Z)-2-(2,4-dioxo-5-((2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidin-3-yl)acetamide

To 10 mg of (Z)-5-((2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was added 4 mg of 2-bromoacetamide, 4 mg of potassium carbonate, and 0.5 mL of DMF. The reaction mixture was heated to 55° C. for 4 h, concentrated under reduced pressure, and purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water gradient using trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) to provide (Z)-2-(2,4-dioxo-5-((2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidin-3-yl)acetamide (4 mg, 11.5 mg theoretical, 35%). LC-MS m/z: 439 (M+1).

Example 85

General Displacement Procedure:

2 dram round-bottomed vials were charged with (Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (25 mg, 0.0877 mmol) prepared according to the general procedure, DMSO (1 mL, 0.08 M), diisopropylethylamine (50 μL, 0.288 mmol, 3.2 equiv.), and the appropriate amine (0.0877 mmol, 1.0 equiv.). The reaction mixture was heated to 110° C. and shaken for 24 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4).

Example 86

(Z)-5-((2-(4-(3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 5-(piperidin-4-yl)-3-(pyridin-4-yl)-1,2,4-oxadiazole (6 mg, 45.8 mg theoretical, 13%). LC-MS m/z 436.4 (M+1).

Example 87

(Z)-5-((2-(butylmethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and N-methylbutan-1-amine (12.5 mg, 30.7 mg theoretical, 40.7%). LC-MS m/z 293.3 (M+1).

Example 88

(Z)-5-((2-(isoquinolin-2(1H)-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure 1,2,3,4-tetrahydroisoquinoline (2 mg, 35 mg theoretical, 5.7%). LC-MS m/z 337.1 (M+1).

Example 89

(Z)-5-((2-(methyl(pyridin-4-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and N-methylpyridin-4-amine (11.7 mg, 32.9 mg theoretical, 35.5%). LC-MS m/z 314.3 (M+1).

Example 90

(Z)-5-((2-(7-amino-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1,2,3,4-tetrahydroisoquinolin-7-amine (12.8 mg, 37.2 mg theoretical, 34.4%). LC-MS m/z 354.3 (M+1).

Example 91

(Z)-5-((2-(3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (4.2 mg, 39.7 mg theoretical, 10.6%). LC-MS m/z 378.4 (M+1).

Example 92

(Z)-5-((2-(((1-methylpiperidin-4-yl)methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-(methylpiperidin-4-yl)methanamine (7.4 mg, 29.2 mg theoretical, 25.3%). LC-MS m/z 334.1 (M+1).

Example 93

(Z)-5-((2-(4-(2-(dimethylamino)ethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and N,N-dimethyl-2-(piperidin-4-yl)ethanamine (20.6 mg, 38.0 mg theoretical, 54.2%). LC-MS m/z 362.2 (M+1).

Example 94

(Z)-5-((2-(4-(1H-indol-3-yl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 3-(piperidin-4-yl)-1H-indole (7.2 mg, 42.6 mg theoretical, 16.8%). LC-MS m/z 406.1 (M+1).

Example 95

(Z)-5-((2-(4-(1H-indol-3-yl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and N,N-dimethyl-1-(piperidin-4-yl)methanamine (23.1 mg, 36.5 mg theoretical, 63.2%). LC-MS m/z 348.1 (M+1).

Example 96

(Z)-5-((2-(3-fluoropiperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 3-fluoropiperidine (7.7 mg, 32.4 mg theoretical, 23.7%). LC-MS m/z 309.1 (M+1).

Example 97

(Z)-5-((2-(4-methylpiperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 4-methylpiperidine (16.4 mg, 32 mg theoretical, 51.2%). LC-MS m/z 305.1 (M+1).

Example 98

(Z)-5-((2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and piperidin-4-ylmethanol (17.8 mg, 33.7 mg theoretical, 52.8%). LC-MS m/z 321.1 (M+1).

Example 99

(Z)-5-((2-(3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 3,5-dimethylpiperidine (1.3 mg, 33.5 mg theoretical, 3.9%). LC-MS m/z 319.1 (M+1).

Example 100

(Z)-5-((2-(8-methyl-2,8-diazaspiro[5.5]undecan-2-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 2-methyl-2,8-diazaspiro[5.5]undecane (23.5 mg, 39.3 mg theoretical, 59.8%). LC-MS m/z 374.2 (M+1).

Example 101

(Z)-5-((2-(3-(piperidin-1-ylmethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-(piperidin-3-ylmethyl)piperidine (21.8 mg, 40.7 mg theoretical, 53.5%). LC-MS m/z 388.5 (M+1).

Example 102

(Z)-5-((2-(2-(2-hydroxyethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 2-(piperidin-2-yl)ethanol (10.1 mg, 35.2 mg theoretical, 28.7%). LC-MS m/z 335.1 (M+1).

Example 103

(Z)-5-((2-(3-(1H-pyrazol-1-yl)azetidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-(azetidin-3-yl)-1H-pyrazole (24.3 mg, 34.5 mg theoretical, 70.4%). LC-MS m/z 329.1 (M+1).

Example 104

(Z)-5-((2-(3-((dimethylamino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and N,N-dimethyl-1-(piperidin-3-yl)methanamine (23.4 mg, 36.5 mg theoretical, 64.1%). LC-MS m/z 348.4 (M+1).

Example 105

(Z)-5-((2-(8-benzyl-2,8-diazaspiro[5.5]undecan-2-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 2-benzyl-2,8-diazaspiro[5.5]undecane (15.3 mg, 47.3 mg theoretical, 32.4%). LC-MS m/z 450.5 (M+1).

Example 106

(Z)-5-((2-(4-(2-hydroxyethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 2-(piperidin-4-yl)ethanol (18.1 mg, 47.2 mg theoretical, 38.4%). LC-MS m/z 335.1 (M+1).

Example 107

(Z)-5-((2-(4-(2-(piperidin-1-yl)ethyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-(2-(piperidin-1-yl)ethyl)piperazine (36.6 mg, 66.3 mg theoretical, 55.2%). LC-MS m/z 403.2 (M+1).

Example 108

(Z)-5-((2-(2-methylpiperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 2-methylpiperidine (2.5 mg, 32 mg theoretical, 7.8%). LC-MS m/z 305.1 (M+1).

Example 109

(Z)-5-((2-(4-hydroxypiperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and piperidin-4-ol (19.9 mg, 33.7 mg theoretical, 52.8%). LC-MS m/z 321.1 (M+1).

Example 110

(Z)-5-((2-(4-fluoropiperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 4-fluoropiperidine (12 mg, 32.4 mg theoretical, 37%). LC-MS m/z 309.1 (M+1).

Example 111

(Z)-5-((2-(3-(pyrrolidin-1-ylmethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 3-(pyrrolidin-1-ylmethyl)piperidine (4.3 mg, 39.3 mg theoretical, 11%). LC-MS m/z 374.5 (M+1).

Example 112

(Z)-5-((2-((2-(dimethylamino)ethyl)(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and N1,N1,N2-trimethylethane-1,2-diamine (5.6 mg, 32.3 mg theoretical, 17.3%). LC-MS m/z 308.4 (M+1).

Example 113

(S,Z)-5-((2-((1-hydroxybutan-2-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and amine (6.6 mg, 30.9 mg theoretical, 21.3%). LC-MS m/z 295.1 (M+1).

Example 114

(Z)-5-((2-(3-(hydroxymethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and (S)-2-aminobutan-1-ol (13.5 mg, 33.7 mg theoretical, 40.1%). LC-MS m/z 321.1 (M+1).

Example 115

(Z)-5-((2-(4,4-bis(hydroxymethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and piperidine-4,4-diyldimethanol (10 mg, 36.8 mg theoretical, 27.1%). LC-MS m/z 351.1 (M+1).

Example 116

(Z)-5-((2-(3-hydroxypiperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and piperidin-3-ol (6.3 mg, 32.2 mg theoretical, 19.6%). LC-MS m/z 307.1 (M+1).

Example 117

(Z)-5-((2-(3-methylpiperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 3-methylpiperidine (10.3 mg, 32 mg theoretical, 32.2%). LC-MS m/z 305.1 (M+1).

Example 118

(S,Z)-5-((2-(methyl(1-methylpiperidin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and (S)—N,1-dimethylpiperidin-3-amine (11.2 mg, 58.4 mg theoretical, 19.2%). LC-MS m/z 334.1 (M+1).

Example 119

(Z)-5-((2-(cyclohexyl(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and N-methylcyclohexanamine (3.4 mg, 33.5 mg theoretical, 10.2%). LC-MS m/z 319.1 (M+1).

Example 120

(Z)-5-((2-(5-amino-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1,2,3,4-tetrahydroisoquinolin-5-amine (8.2 mg, 37.2 mg theoretical, 22%). LC-MS m/z 354.1 (M+1).

Example 121

(Z)-5-((2-(cyclohexylamino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and cyclohexanamine (3.6 mg, 32 mg theoretical, 11.2%). LC-MS m/z 305.1 (M+1).

Example 122

(Z)-1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidine-4-carboxamide was prepared using the general displacement procedure and piperidine-4-carboxamide (16.7 mg, 35.1 mg theoretical, 47.6%). LC-MS m/z 334.1 (M+1).

Example 123

(Z)-5-((2-((4-(m-tolylamino)-5,6,7,8-tetrahydroquinazolin-6-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and N4-(m-tolyl)-5,6,7,8-tetrahydroquinazoline-4,6-diamine (5.2 mg, 48.3 mg theoretical, 10.8%). LC-MS m/z 460.5 (M+1).

Example 124

(Z)-5-((2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (12.4 mg, 38.2 mg theoretical, 32.4%). LC-MS m/z 437.1 (M+1).

Example 125

(Z)-5-((2-(3-(3-ethyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 3-ethyl-5-(piperidin-3-yl)-1,2,4-oxadiazole (11.9 mg, 33.9 mg theoretical, 35.1%). LC-MS m/z 387.1 (M+1).

Example 126

(Z)-5-((2-(4-(4,6-diamino-1,3,5-triazin-2-yl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 6-(piperidin-4-yl)-1,3,5-triazine-2,4-diamine (13.0 mg, 35.0 mg theoretical, 37.1%). LC-MS m/z 400.1 (M+1).

Example 127

(Z)-5-((2-(3-((1H-benzo[d]imidazol-2-yl)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 2-(piperidin-3-ylmethyl)-1H-benzo[d]imidazole (29.3 mg, 44.2 mg theoretical, 66.3%). LC-MS m/z 421.5 (M+1).

Example 128

(Z)-5-((2-(3-(4-methyl-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 4-methyl-2-(piperidin-3-yl)-1H-benzo[d]imidazole (18.9 mg, 44.2 mg theoretical, 42.7%). LC-MS m/z 421.5 (M+1).

Example 129

(Z)-5-((2-(4-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 3-(piperidin-4-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine (16.2 mg, 44.7 mg theoretical, 36.2%). LC-MS m/z 426.5 (M+1).

Example 130

(Z)-5-((2-(((1-ethyl-1H-pyrazol-5-yl)methyl)(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-(1-ethyl-1H-pyrazol-5-yl)-N-methylmethanamine (7.2 mg, 36.2 mg theoretical, 20%). LC-MS m/z 345.1 (M+1).

Example 131

(Z)-5-((2-(3-(6-hydroxy-2-methylpyrimidin-4-yl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 2-methyl-6-(piperidin-3-yl)pyrimidin-4-ol (16.8 mg, 41.9 mg theoretical, 40.1%). LC-MS m/z 399.1 (M+1).

Example 132

(Z)-5-((2-(3-([1,2,4]triazolo[4,3-a]pyridin-3-yl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 3-(piperidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine (11 mg, 42.8 mg theoretical, 25.7%). LC-MS m/z 408.5 (M+1).

Example 133

(Z)-5-((2-(4-amino-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1,2,3,4-tetrahydroisoquinolin-4-amine (1.4 mg, 37.2 mg theoretical, 3.8%). LC-MS m/z 354.1 (M+1).

Example 134

(Z)-5-((2-(4-(1H-tetrazol-5-yl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 4-(1H-tetrazol-5-yl)piperidine (4 mg, 37.7 mg theoretical, 10.6%). LC-MS m/z 359.1 (M+1).

Example 135

(Z)-5-((2-(methyl(thiophen-3-ylmethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and N-methyl-1-(thiophen-3-yl)methanamine (7.5 mg, 35 mg theoretical, 21.5%). LC-MS m/z 333.0 (M+1).

Example 136

(Z)-5-((2-(2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1,3,8-triazaspiro[4.5]decane-2,4-dione (15.2 mg, 39.4 mg theoretical, 38.6%). LC-MS m/z 375.1 (M+1).

Example 137

(Z)-5-((2-(((1H-benzo[d]imidazol-2-yl)methyl)(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1-(1H-benzo[d]imidazol-2-yl)-N-methylmethanamine (6.6 mg, 38.5 mg theoretical, 17%). LC-MS m/z 367.1 (M+1).

Example 138

(Z)-5-((2-((3-aminobenzyl)(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 3-((methylamino)methyl)aniline (19.7 mg, 35.9 mg theoretical, 54.9%). LC-MS m/z 342.1 (M+1).

Example 139

(Z)-5-((2-((2-(1H-indol-3-yl)ethyl)(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 2-(1H-indol-3-yl)-N-methylethanamine (8.3 mg, 39.9 mg theoretical, 20.8%). LC-MS m/z 380.4 (M+1).

Example 140

(Z)-5-((2-((1,2,3,4-tetrahydroquinolin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 1,2,3,4-tetrahydroquinolin-3-amine (5 mg, 37.2 mg theoretical, 13.5%). LC-MS m/z 354.1 (M+1).

Example 141 Displacement/De-Protection of Mono-Boc Diamines

Example 142

(R,Z)-5-((2-(methyl(piperidin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and (R)-tert-butyl 3-(methylamino)piperidine-1-carboxylate. The crude protected amine was then treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (3.1 mg, 55.9 mg theoretical, 5.5%). LC-MS m/z 320.1 (M+1).

Example 143

(S,Z)-5-((2-(methyl(piperidin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and (S)-tert-butyl 3-(methylamino)piperidine-1-carboxylate. The crude protected amine was then treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (3.2 mg, 55.9 mg theoretical, 5.7%). LC-MS m/z 320.1 (M+1).

Example 144

(S,Z)-5-((2-(piperidin-3-ylamino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and (R)-tert-butyl 3-aminopiperidine-1-carboxylate. The crude protected amine was then treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (6.9 mg, 32.1 mg theoretical, 21.5%). LC-MS m/z 306.1 (M+1).

Example 145

(R,Z)-5-((2-(piperidin-3-ylamino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and (S)-tert-butyl 3-aminopiperidine-1-carboxylate. The crude protected amine was then treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (3.8 mg, 32.1 mg theoretical, 11.8%). LC-MS m/z 306.1 (M+1).

Example 146

(Z)-5-((2-((piperidin-2-ylmethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and tert-butyl 2-(aminomethyl)piperidine-1-carboxylate. The crude protected amine was then treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (10.7 mg, 45.6 mg theoretical, 23.5%). LC-MS m/z 320.1 (M+1).

Example 147

(Z)-5-((2-((piperidin-4-ylmethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate. The crude protected amine was then treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (5.3 mg, 33.5 mg theoretical, 15.8%). LC-MS m/z 320.1 (M+1).

Example 148

(R,Z)-5-((2-((piperidin-3-ylmethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and (S)-tert-butyl 3-(aminomethyl)piperidine-1-carboxylate. The crude protected amine was then treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (7.3 mg, 33.5 mg theoretical, 21.8%). LC-MS m/z 320.1 (M+1).

Example 149

(Z)-5-((2-(methyl(piperidin-3-ylmethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and tert-butyl 3-((methylamino)methyl)piperidine-1-carboxylate. The crude protected amine was then treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (21.6 mg, 35 mg theoretical, 61.7%). LC-MS m/z 334.1 (M+1).

Example 150

(Z)-5-((2-(3-((methylamino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and tert-butyl methyl(piperidin-3-ylmethyl)carbamate. The crude protected amine was then treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (17.9 mg, 35 mg theoretical, 51.1%). LC-MS m/z 334.1 (M+1).

Example 151

(Z)-5-((2-(methyl(piperidin-4-ylmethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and tert-butyl 4-((methylamino)methyl)piperidine-1-carboxylate. The crude protected amine was then treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (6.5 mg, 35 mg theoretical, 18.6%). LC-MS m/z 334.1 (M+1).

Example 152

(S,Z)-5-((2-((piperidin-3-ylmethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and (R)-tert-butyl 3-((methylamino)methyl)piperidine-1-carboxylate. The crude protected amine was then treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (11.2 mg, 33.5 mg theoretical, 33.4%). LC-MS m/z 320.1 (M+1).

Example 153

(Z)-5-((2-((2-aminoethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and tert-butyl (2-aminoethyl)carbamate. The crude protected amine was then treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (10.7 mg, 27.9 mg theoretical, 38.4%). LC-MS m/z 266.1 (M+1).

Example 154

(Z)-5-((2-(3-(methylamino)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and tert-butyl methyl(piperidin-3-yl)carbamate. The crude protected amine was then treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (26.9 mg, 33.5 mg theoretical, 80%). LC-MS m/z 320.1 (M+1).

Example 155

(Z)-5-((2-(octahydro-1,5-naphthyridin-1(2H)-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and tert-butyl octahydro-1,5-naphthyridine-1(2H)-carboxylate. The crude protected amine was then treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (7.2 mg, 36.3 mg theoretical, 19.8%). LC-MS m/z 346.1 (M+1).

Example 156

(Z)-5-((2-((3-aminobenzyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and tert-butyl (3-(aminomethyl)phenyl)carbamate. The crude protected amine was then treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (6.5 mg, 28.7 mg theoretical, 22.7%). LC-MS m/z 328.1 (M+1).

Example 157

(Z)-5-((2-((5-phenylpiperidin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and tert-butyl 3-amino-5-phenylpiperidine-1-carboxylate. The crude protected amine was then treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (5.6 mg, 33.4 mg theoretical, 16.8%). LC-MS m/z 382.1 (M+1).

Example 158

(Z)-5-((2-((4-phenylpiperidin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and tert-butyl 3-amino-4-phenylpiperidine-1-carboxylate. The crude protected amine was then treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (5.7 mg, 33.4 mg theoretical, 17.1%). LC-MS m/z 382.1 (M+1).

Example 159

(Z)-5-((2-((3-(aminomethyl)benzyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and tert-butyl 3-(aminomethyl)benzylcarbamate. The crude protected amine was then treated with 2 mL DCE and 500 μLof TFA and shaken for 24 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (16.6 mg, 35.8 mg theoretical, 46.3%). LC-MS m/z 342.1 (M+1).

Example 160

(Z)-5-((2-(octahydro-1,5-naphthyridin-1(2H)-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 3-((tert-butoxycarbonyl)amino)-3-(piperidin-4-yl)propanoic acid. The crude protected amine was then treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (24.6 mg, 11.8 mg theoretical, 208%). LC-MS m/z 378.4 (M+1).

Example 161

(S,Z)-5-((2-(3-aminopiperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and (S)-tert-butyl piperidin-3-ylcarbamate. The crude protected amine was then treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (46.8 mg, 30.2 mg theoretical, 155%). LC-MS m/z 306.1 (M+1).

Example 162

(R,Z)-5-((2-(3-aminopiperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and (R)-tert-butyl piperidin-3-ylcarbamate. The crude protected amine was then treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) (44.2 mg, 30.2 mg theoretical, 146%). LC-MS m/z 306.1 (M+1).

Example 163

(Z)-5-((6-(methyl(piperidin-3-yl)amino)-2-(piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using General Procedure 2 for the Preparation of Amino-Analogs (Example 81) using tert-butyl 3-(methylamino)piperidine-1-carboxylate and piperidine (11.4 mg, 54.0 mg theoretical, 21.1%). LC-MS m/z 403.2 (M+1).

Example 164

(Z)-5-((2-(methyl(piperidin-3-yl)amino)-6-(piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using General Procedure 2 for the Preparation of Amino-Analogs (Example 81) using piperidine and tert-Butyl 3-(methylamino)piperidine-1-carboxylate (10.5 mg, 26.3 mg theoretical, 41.9%). LC-MS m/z 403.2 (M+1).

Example 165

(Z)-5-((2,6-di(piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using General Procedure 2 for the Preparation of Amino-Analogs (Example 81) using piperidine (14.0 mg, 233 mg theoretical, 6%). LC-MS m/z 374.2 (M+1).

Example 166

(Z)-5-((2-(4-(aminomethyl)piperidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared as follows.

4-Methyl-2-(methylthio)-6-(trifluoromethyl)pyrimidine

A 30 mL round-bottomed vial was charged with 1,1,1-trifluoropentane-2,4-dione (2.00 g, 13.0 mmol, 1 equiv.), ethanol (15 mL, 0.8 M), thiomethylisourea hemi sulfuric acid salt (1.807 g, 6.5 mmol, 1 equiv.) and the reaction mixture was shaken at 80° C. for 3 h. The solvent was concentrated under reduced pressure and the residue was partitioned between CH₂Cl₂ (25 mL) and saturated NaHCO₃ (25 mL). The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organic layer was dried over Na₂SO₄ and concentrated under reduced pressure to provide the crude desired pyrimidine as a slightly orange solid. Purification using the Biotage (SiO₂, 25 g cartridge, Hexanes/EtOAc 95:5 to 75:25) afforded 1.66 g of the pure desired product (2.70 g theoretical, 61.4%). LC-MS m/z 209 (M+1).

(Z)-5-((2-(Methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione

A 30 mL round-bottomed vial was charged with 4-methyl-2-(methylthio)-6-(trifluoromethyl)pyrimidine (0.500 g, 2.4 mmol, 1 equiv.), ethanol (5 mL, 0.48 M), selenium dioxide (0.293 mg, 2.6 mmol, 1.1 equiv.), and the reaction mixture was shaken at 90° C. for 40 h and then RT for 14 d. The crude reaction mixture was then treated with thiazolidine-2,4-dione (0.281 g, 2.4 mmol, 1 equiv.), triethylamine (1.0 mL, 7.20 mmol, 3 equiv.) and the reaction mixture was shaken for 16 h at 80° C. The solvent was concentrated under reduced pressure and the residue was partitioned between EtOAc (30 mL) and saturated NaHCO₃ (25 mL). The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified using the Biotage (SiO₂, 10 g cartridge, CH₂Cl₂/MeOH 99:1 to 9:1) that afforded 270 mg of partially purified product that was re-purified using the Biotage (SiO₂, 10 g cartridge, Hexanes/EtOAc 90:10 to 0:1 then CH₂Cl₂/MeOH 99:1 to 9:1) afforded 212 mg of yellow solid that was still not completely pure but was used directly in the next step without further purification.

(Z)-5-((2-(Methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione

An 8 mL round-bottomed vial was charged with the pyrimidine sulfide (212 mg, 0.66 mmol, 1 equiv.), CH₂Cl₂ (3 mL, 0.22 M), m-CPBA 50% by weight (0.683 g, 1.98 mmol, 3 equiv.) was added over a 1 min. period at RT. After 3.5 h, an additional 3 equivalents of m-CPBA 50% by weight (0.683 g, 1.98 mmol, 3 equiv.) was added and the reaction mixture was stirred at RT overnight. The resulting white solid was filtered and washed with CH₂Cl₂ and then with Et₂O to provide 67 mg of an off-white solid (233 mg theoretical, 28.7%), which was used in the next step without further purification. LC-MS m/z 354 (M+1).

(Z)-tert-Butyl ((1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)methyl)carbamate

An 8 mL round-bottomed vial was charged with the 2-sulfone pyrimidine (67 mg, 0.19 mmol, 1 equiv.), DMSO (1 mL, 0.19M), tert-Butyl (piperidin-4-ylmethyl)carbamate (40.6 mg, 0.19 mmol, 1 equiv.), DIPEA (66 μL, 0.38 mmol, 2 equiv.), and the reaction mixture was stirred for 1 h at RT and then 50° C. for 3 h. The reaction was directly purified using reverse phase HPLC (2 injections of 500 μL, 12 min method, methanol/water gradient with 0.4% TFA) to afford the desired product (15.3 mg, 92.7 mg theoretical, 16.5%).

(Z)-5-((2-(4-(aminomethyl)piperidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione

An 8 mL round-bottomed vial was charged with the CF₃-pyrimidine (15.3 mg, 0.031 mmol, 1 equiv.), CH₂Cl₂ (1 mL, 0.03 M), TFA (0.5 mL, 6.5 mmol, 208 equiv.), and the reaction mixture was stirred for 1 h at RT. The solvent was concentrated under reduced pressure and the residue was dried under high vacuum. The residue was washed with ether (2×2 mL) and the yellow solid was dried under high vacuum overnight to afford (13.4 mg, 15.8 mg theoretical, 85%). LC-MS m/z 388.1 (M+1).

Example 167

(Z)-5-((2-(4-(aminomethyl)piperidin-1-yl)-6-methoxypyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared as follows.

Methyl 2-chloro-6-methoxypyrimidine-4-carboxylate

A 30 mL round-bottomed vial was charged with methyl 2,6-dichloropyrimidine-4-carboxylate (0.6 g, 2.9 mmol, 1 equiv.), methanol (6 mL, 0.97 M), K₂CO₃ (0.401 g, 2.9 mmol, 1 equiv.), and the reaction mixture was shaken at 65° C. for 1.5 h. The solvent was concentrated under reduced pressure and the residue was partitioned between EtOAc (25 mL) and H₂O (25 mL) and the water layer was extracted with EtOAc (2×20 mL). The combined organic layer was dried over Na₂SO₄ and concentrated under reduced pressure to provide the crude chloropyrimidine (441 mg, 588 mg theoretical, 75%), which was used in the next step without further purification.

Methyl 2-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)-6-methoxypyrimidine-4-carboxylate

An 8 mL round-bottomed vial was charged with the 2-chloropyrimidine (150 mg, 0.74 mmol, 1.5 equiv.), methanol (1.5 mL, 0.49 M), tert-Butyl (piperidin-4-ylmethyl)carbamate (159 mg, 0.49 mmol, 1 equiv.), DIPEA (258 μL, 0.99 mmol, 2 equiv.), and the reaction mixture was shaken at 65° C. for 3 h. The solvent was concentrated under reduced pressure and the residue was partitioned between EtOAc (25 mL) and saturated NaHCO₃ (10 mL). The organic layer was dried over Na₂SO₄ and dried under reduced pressure to provide the crude product. Purification using the Biotage (SiO₂, 10 g cartridge, Hexanes/EtOAc 95:5 to 40:60) afforded the desired pyrimidine intermediate as a white solid (219 mg, 281 mg theoretical, 78%).

tert-Butyl ((1-(4-formyl-6-methoxypyrimidin-2-yl)piperidin-4-yl)methyl)carbamate

A 50 mL 2-neck round-bottomed flask was charged with the methyl ester intermediate (150 mg, 0.39 mmol, 1 equiv.), CH₂Cl₂ (2 mL, 0.195 M), and then DIBAL-H 1 M in CH₂Cl₂ (0.59 mL, 0.59 mmol, 1.5 equiv.) was added over a 4 minute period at −78° C. The reaction was then stirred for 1.5 h at −78° C. and for 1.5 h between −78° C. and RT. LC-MS showed mostly starting material so the reaction mixture was re-cooled to −78° C. and DIBAL-H (0.8 mL, 0.8 mmol, 2 equiv.) was added. LC-MS showed mostly starting material. The reaction mixture was stored at −20° C. for 3 d. The reaction mixture was cooled to −78° C. and treated with 1M DIBAL-H in hexanes (0.59 mL, 0.59 mmol, 1 equiv.) over a 5 min. period, which produced a white precipitate. After 2.5 h, another equivalent of DiBAL-H (1 M in Hexanes, 0.59 mL) was added over a 15 min. period at −78° C. The reaction was quenched at −78° C. after 35 min. with methanol (1 mL). The solvent were concentrated under reduced pressure and the residue was partitioned between CH₂Cl₂ (20 mL) and saturated NaHCO₃ (20 mL). The organic layer was dried over Na₂SO₄ and the solvent was concentrated under reduced pressure to provide the crude product, which was used in the next step without further purification.

(Z)-tert-Butyl ((1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-6-methoxypyrimidin-2-yl)piperidin-4-yl)methyl)carbamate

An 8 mL round-bottomed vial was charged with the crude aldehyde (0.2 mmol, estimated), ethanol (2 mL), thiazolidine-2,4-dione (23 mg, 0.2 mmol, 1 equiv.), triethylamine (56 μL, 0.4 mmol, 2 equiv.), purged with Ar, and the reaction mixture was shaken at 80° C. for 24 h. The crude mixture was purified using the Biotage (SiO₂, 10 g cartridge, CH₂Cl₂/MeOH 99:1 to 94:6) afforded 113 mg of the partially purified product. The sample was re-purified using reverse phase HPLC (methanol/water 10-90%, 0.4% TFA, 3 equal injections) provided the pure product as a TFA salt (47.3 mg, 225 mg theoretical, 21%). LC-MS m/z 450 (M+1).

(Z)-5-((2-(4-(aminomethyl)piperidin-1-yl)-6-methoxypyrimidin-4-yl)methylene)thiazolidine-2,4-dione

An 8 mL round-bottomed vial was charged with the MeO-pyrimidine boc protected amine (47.3 mg, 105 μmol, 1 equiv.), CH₂Cl₂ (1.3 mL, 0.08 M), TFA (0.5 mL, 6.5 mmol, 62 equiv.), and the reaction mixture was stirred for 1 h at RT. The solvents were concentrated under reduced pressure and the residue was re-dissolved in DMSO (0.9 mL) and purified by reverse phase HPLC (methanol/water with 0.4% TFA, 10-90% method, 2 injections of 500 μL) to provide as the TFA salt (43.9 mg, 48.8 mg theoretical, 90%). LC-MS m/z 350.1 (M+1).

Example 168 Synthesized Pyridine Analogs

(Z)-5-((6-(piperidin-1-yl)pyridin-2-yl)methylene)thiazolidine-2,4-dione was prepared as follows.

A 30 mL round-bottomed vial was charged with thiazolidine-2,4-dione (300 mg, 2.56 mmol, 1 equiv.), toluene (5 mL, 0.5 M), 6-bromopicolinaldehyde (477 mg, 2.56 mmol, 1 equiv.), glacial acetic acid (22 μL, 0.256 mmol, 0.1 equiv.), piperidine (25 μL, 0.256 mmol, 0.1 equiv.), purged with Ar, and heated with shaking at 125° C. After heating for 16 h, the yellow reaction solution was pipeted away from the solid precipitate. The precipitate was washed with acetone (3×5 mL) and dried under high vacuum to afford the desired product as a solid (439 mg, 731 mg theoretical, 60%), which was used in the next step without further purification.

A 2 dram round-bottomed vial was charged with (Z)-5-((6-bromopyridin-2-yl)methylene)thiazolidine-2,4-dione (60 mg, 0.210 mmol, 1 equiv.), DMSO (1 mL, 0.08 M), diisopropylethylamine (34 μL, 0.2 mmol, 1 equiv.), and piperidine (21 μL, 0.21 mmol, 1 equiv.), and the reaction was heated with shaking at 110° C. for 24 h. The solvent was removed under reduced pressure (Genvac HT-4) and the crude residue was purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) to provide (Z)-5-((6-(piperidin-1-yl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (7.9 mg, 60.9 mg theoretical, 12.9%). LC-MS m/z 290.1 (M+1).

Example 169 Synthesized Reductive Amination Analogs

General Reductive Amination Procedure:

A 2-dram round-bottomed vial was charged with the crude amine/TFA salt prepared using the general displacement procedure followed by the general TFA de-protection procedure (0.115 mmol), DCE (2 mL), DIPEA (6 eq. 0.690 mmol), DMF (1 mL), the aldehyde (1 equiv., 0.115 mmol), and the reaction mixture was shaken for 1 h at RT. The reaction mixture was then treated with NaBH(OAc)₃ (2.5 equiv., 0.230 mmol) and the reaction was shaken 16 h at RT. The reaction mixture was then diluted with DCE (2 mL) and NaHCO₃ (2 mL). The aqueous layer was back extracted with DCE (2×2 mL) and the combined organic layer was concentrated under reduced pressure (Genevac HT-4) and the crude residue was purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as the modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) to afford the pure products as the TFA salt.

Example 170

(Z)-5-((2-((2-(dimethylamino)ethyl)(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and picolinaldehyde (16.1 mg, 47 mg theoretical, 34.3%). LC-MS m/z 448.5 (M+1).

Example 171

(Z)-5-((2-((2-((3-chlorobenzyl)amino)ethyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general General Reductive Amination Procedure (Example 169) and 3-chlorobenzaldehyde (5.6 mg, 40.9 mg theoretical, 13.7%). LC-MS m/z 390.8 (M+1).

Example 172

(Z)-5-((2-(4-(((pyridin-2-ylmethyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and picolinaldehyde (8.5 mg, 71.8 mg theoretical, 11.8%). LC-MS m/z 411.5 (M+1).

Example 173

(S,Z)-5-((2-((1-(pyridin-2-ylmethyl)piperidin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and picolinaldehyde (2.6 mg, 34.7 mg theoretical, 7.1%). LC-MS m/z 397.1 (M+1).

Example 174

(Z)-5-((2-(4-((((6-methylpyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and 6-methylpicolinaldehyde (10.4 mg, 74.3 mg theoretical, 14%). LC-MS m/z 425.5 (M+1).

Example 175

(Z)-5-((2-(4-((bis((6-methylpyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and 6-methylpicolinaldehyde (2.5 mg, 92.6 mg theoretical, 2.7%). LC-MS m/z 530.6 (M+1).

Example 176

(Z)-5-((2-(4-(((pyridin-3-ylmethyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and nicotinaldehyde (5.3 mg, 71.8 mg theoretical, 7.4%). LC-MS m/z 411.5 (M+1).

Example 177

(Z)-5-((2-(4-(((pyridin-4-ylmethyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and isonicotinaldehyde (4.1 mg, 71.8 mg theoretical, 5.7%). LC-MS m/z 411.5 (M+1).

Example 178

(S,Z)-5-((2-((1-(quinolin-2-ylmethyl)piperidin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and quinoline-2-carbaldehyde (2.2 mg, 78 mg theoretical, 2.8%). LC-MS m/z 447.5 (M+1).

Example 179

(S,Z)-5-((2-((1-(isoquinolin-3-ylmethyl)piperidin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and isoquinoline-3-carbaldehyde (1.5 mg, 78 mg theoretical, 1.9%). LC-MS m/z 447.5 (M+1).

Example 180

(Z)-5-((2-(4-(((quinolin-2-ylmethyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and quinoline-2-carbaldehyde (3.8 mg, 81 mg theoretical, 4.7%). LC-MS m/z 461.5 (M+1).

Example 181

(Z)-5-((2-(4-((((2-methylquinolin-4-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and 2-methylquinoline-4-carbaldehyde (35.1 mg, 56.5 mg theoretical, 62.2%). LC-MS m/z 475.5 (M+1).

Example 182

(Z)-5-((2-(4-(((isoquinolin-1-ylmethyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and isoquinoline-1-carbaldehyde (35.1 mg, 43.8 mg theoretical, 80%). LC-MS m/z 461.5 (M+1).

Example 183

(Z)-5-((2-(4-((((6-methoxypyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and 6-methoxypicolinaldehyde (37.5 mg, 52.4 mg theoretical, 71.5%). LC-MS m/z 441.5 (M+1).

Example 184

(Z)-5-((2-(4-((((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and 5-(trifluoromethyl)picolinaldehyde (23 mg, 56.9 mg theoretical, 40.4%). LC-MS m/z 479.5 (M+1).

Example 185

(Z)-5-((2-(4-((((6-fluoropyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and 6-fluoropicolinaldehyde (29.3 mg, 51 mg theoretical, 57.5%). LC-MS m/z 429.5 (M+1).

Example 186

(Z)-5-((2-(4-((((2-(piperidin-1-yl)pyrimidin-5-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and 2-(piperidin-1-yl)pyrimidine-5-carbaldehyde (40.1 mg, 47 mg theoretical, 80%). LC-MS m/z 495.5 (M+1).

Example 187

(Z)-5-((2-(4-((((3-(trifluoromethyl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and 3-(trifluoromethyl)picolinaldehyde (44 mg, 45.5 mg theoretical, 97%). LC-MS m/z 479.5 (M+1).

Example 188

(Z)-5-((2-(4-((((3-fluoropyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and 3-fluoropicolinaldehyde (42.5 mg, 40.7 mg theoretical, 104%). LC-MS m/z 429.5 (M+1).

Example 189

(Z)-5-((2-(4-((((8-methoxyquinolin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and 8-methoxyquinoline-2-carbaldehyde (35.5 mg, 46.6 mg theoretical, 76%). LC-MS m/z 491.5 (M+1).

Example 190

(Z)-5-((2-(4-((((8-fluoroquinolin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and 8-fluoroquinoline-2-carbaldehyde (28.5 mg, 45.5 mg theoretical, 62.7%). LC-MS m/z 479.5 (M+1).

Example 191

(Z)-5-((2-(4-((((6-fluoroquinolin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and 6-fluoroquinoline-2-carbaldehyde (32.7 mg, 45.5 mg theoretical, 71.9%). LC-MS m/z 479.5 (M+1).

Example 192

(Z)-5-((2-(4-((pyridin-2-ylamino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and 2-chloroisonicotinaldehyde (19.6 mg, 42.3 mg theoretical, 46.4%). LC-MS m/z 445.5 (M+1).

Example 193

(Z)-5-((2-(4-((((5-fluoropyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and 5-fluoropicolinaldehyde (7.9 mg, 40.7 mg theoretical, 19.4%). LC-MS m/z 429.5 (M+1).

Example 194

(Z)-5-((2-(4-(((quinolin-4-ylmethyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and quinoline-4-carbaldehyde (24.6 mg, 43.8 mg theoretical, 56.2%). LC-MS m/z 461.5 (M+1).

Example 195

(Z)-5-((2-(4-((((1,8-naphthyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and 1,8-naphthyridine-2-carbaldehyde (6.9 mg, 43.8 mg theoretical, 15.7%). LC-MS m/z 462.5 (M+1).

Example 196

(S,Z)-5-((2-(3-((quinolin-2-ylmethyl)amino)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and quinoline-2-carbaldehyde (30.9 mg, 54.9 mg theoretical, 56.3%). LC-MS m/z 447.2 (M+1).

Example 197

(S,Z)-5-((2-(3-(((6-fluoroquinolin-2-yl)methyl)amino)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and 6-fluoroquinoline-2-carbaldehyde (26.7 mg, 57.1 mg theoretical, 46.7%). LC-MS m/z 465.5 (M+1).

Example 198

(S,Z)-5-((2-(3-(((8-methoxyquinolin-2-yl)methyl)amino)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and 8-methoxyquinoline-2-carbaldehyde (16.4 mg, 58.6 mg theoretical, 28%). LC-MS m/z 477.5 (M+1).

Example 199

(R,Z)-5-((2-(3-((quinolin-2-ylmethyl)amino)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169)e and quinoline-2-carbaldehyde (24.9 mg, 54.9 mg theoretical, 45.3%). LC-MS m/z 447.5 (M+1).

Example 200

(R,Z)-5-((2-(3-(((6-fluoroquinolin-2-yl)methyl)amino)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and 6-fluoroquinoline-2-carbaldehyde (24.1 mg, 57.1 mg theoretical, 42.2%). LC-MS m/z 465.5 (M+1).

Example 201

(R,Z)-5-((2-(3-(((8-methoxyquinolin-2-yl)methyl)amino)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and 8-methoxyquinoline-2-carbaldehyde (15.5 mg, 58.6 mg theoretical, 26.4%). LC-MS m/z 477.5 (M+1).

Example 202

(R,Z)-5-((2-(3-(((2-methylquinolin-4-yl)methyl)amino)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and 2-methylquinoline-4-carbaldehyde (25 mg, 56.6 mg theoretical, 44.1%). LC-MS m/z 461.5 (M+1).

Example 203

(S,Z)-5-((2-(3-(((2-methylquinolin-4-yl)methyl)amino)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and 2-methylquinoline-4-carbaldehyde (30 mg, 56.6 mg theoretical, 53%). LC-MS m/z 461.5 (M+1).

Example 204

(Z)-5-((2-(4-((((6-(4-fluorophenyl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and 6-(4-fluorophenyl)picolinaldehyde (26.5 mg, 36.3 mg theoretical, 72.9%). LC-MS m/z 505.5 (M+1).

Example 205

(Z)-5-((2-(4-((((6-(thiophen-2-yl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and 6-(thiophen-2-yl)picolinaldehyde (15.2 mg, 35.5 mg theoretical, 42.9%). LC-MS m/z 493.5 (M+1).

Example 206

(Z)-5-((2-(4-((((6-(benzo[d][1,3]dioxol-5-yl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and 6-(benzo[d][1,3]dioxol-5-yl)picolinaldehyde (25.8 mg, 38.2 mg theoretical, 67.5%). LC-MS m/z 531.5 (M+1).

Example 207

(Z)-5-((2-(4-((((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and 6-(thiophen-3-yl)picolinaldehyde (32.5 mg, 35.5 mg theoretical, 92%). LC-MS m/z 493.5 (M+1).

Example 208

(Z)-5-((2-(4-(((azetidin-2-ylmethyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and tert-butyl 2-formylazetidine-1-carboxylate followed by the general TFA de-protection procedure (15.2 mg, 68 mg theoretical, 22.4%). LC-MS m/z 389.5 (M+1).

Example 209

(Z)-5-((2-(4-(((pyrrolidin-3-ylmethyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and tert-butyl 3-formylpyrrolidine-1-carboxylate followed by the general TFA de-protection procedure (17.1 mg, 70.4 mg theoretical, 24%). LC-MS m/z 403.5 (M+1).

Example 210

(Z)-5-((2-(((3S)-1-(pyrrolidin-3-ylmethyl)piperidin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and tert-butyl 3-formylpyrrolidine-1-carboxylate followed by the general TFA de-protection procedure (2.7 mg, 34.0 mg theoretical, 7.9%). LC-MS m/z 389.2 (M+1).

Example 211

(Z)-5-((2-(4-(((piperidin-3-ylmethyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and tert-butyl 3-formylpiperidine-1-carboxylate followed by the general TFA de-protection procedure (26.5 mg, 72.9 mg theoretical, 36.4%). LC-MS m/z 417.2 (M+1).

Example 212

(Z)-5-((2-(((3S)-1-(azetidin-2-ylmethyl)piperidin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and tert-butyl 2-formylazetidine-1-carboxylate followed by the general TFA de-protection procedure (2.2 mg, 32.8 mg theoretical, 6.0%). LC-MS m/z 375.2 (M+1).

Example 213

(Z)-5-((2-(((3S)-1-(piperidin-3-ylmethyl)piperidin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reductive Amination Procedure (Example 169) and tert-butyl 3-formylpiperidine-1-carboxylate followed by the general TFA de-protection procedure (4.5 mg, 35.3 mg theoretical, 11.9%). LC-MS m/z 403.2 (M+1).

Example 214

General Reverse Reductive Amination Procedure:

A 2-dram round-bottomed vial was charged with tert-butyl 4-formylpiperidine-1-carboxylate (0.7 mmol), the amine (1 equiv., 0.7 mmol), DCE (3 mL), and shaken for 1 h at RT. The reaction mixture was then treated with NaBH(OAc)₃ (2 equiv., 1.4 mmol) and shaken for 16 h at RT. The reaction mixture was then washed with saturated NaHCO₃ (3 mL) and the aqueous layer was back extracted with DCE (2×2 mL. The combined organic layer was concentrated under reduced pressure (GeneVac HT-4) and the crude residue was purified by HPLC using a MeOH/H₂O gradient with TFA as the modifier. The resulting Boc-protected piperidine analog was treated with DCE (3 mL), TFA (0.5 mL), and shaken at RT for 2 h. The reaction mixture was concentrated under reduced pressure (GeneVac HT-4) and used in the general displacement procedure without further purification.

Example 215

(Z)-5-((2-(4-((pyridin-3-ylamino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reverse Reductive Amination Procedure (Example 214) and pyridin-3-amine (15.5 mg, 41.7 mg theoretical, 37.2%). LC-MS m/z 397.5 (M+1).

Example 216

(Z)-5-((2-(4-(((4-morpholinophenyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reverse Reductive Amination Procedure (Example 214) and 4-morpholinoaniline (12.5 mg, 50.5 mg theoretical, 24.7%). LC-MS m/z 481.5 (M+1).

Example 217

(Z)-5-((2-(4-((pyridin-2-ylamino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reverse Reductive Amination Procedure (Example 214) and pyridin-2-amine (21.2 mg, 41.7 mg theoretical, 50.9%). LC-MS m/z 397.5 (M+1).

Example 218

(Z)-5-((2-(4-((((1H-benzo[d]imidazol-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reverse Reductive Amination Procedure (Example 214) and (1H-benzo[d]imidazol-2-yl)methanamine (8 mg, 42.7 mg theoretical, 18.7%). LC-MS m/z 450.5 (M+1).

Example 219

(Z)-5-((2-(4-((quinolin-2-ylamino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the General Reverse Reductive Amination Procedure (Example 214) and quinolin-2-amine (21.2 mg, 128 mg theoretical, 16.53%). LC-MS m/z 447.5 (M+1).

Example 220

(Z)—N-(1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)pyrrolidin-3-yl)furan-2-carboxamide was prepared as follows.

A 2-dram round-bottomed vial was charged with (Z)-5-((2-(3-aminopyrrolidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione, prepared using the general displacement procedure followed by the general TFA de-protection procedure, (25 mg, 0.065 mmol), DCM (1 mL), furan-2-carbonyl chloride (8 μL, 0.082 mmol, 1.3 equiv.), and pyridine (0.040 mL, 0.491 mmol, 7.5 equiv.). The reaction mixture was shaken at RT for 16 h, the solvent was removed under reduced pressure (Genevac HT-4), and the crude residue was purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water gradient and trifluoroacetic acid as the modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) to provide the title compound (2.7 mg, 33.1 mg theoretical, 8.2%). LC-MS m/z 386.1 (M+1).

Example 221

(Z)-5-((2-(4-(furan-2-carbonyl)-1,4-diazepan-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared as follows.

A 2-dram round-bottomed vial was charged with (Z)-5-((2-(1,4-diazepan-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione, prepared using the general displacement procedure followed by the general TFA de-protection procedure, (25 mg, 0.062 mmol), DCM (1 mL), furan-2-carbonyl chloride (8.07 μL, 0.062 mmol, 1 equiv.), and pyridine (0.040 mL, 0.491 mmol, 8 equiv.). The reaction mixture was shaken at RT for 16 h, the solvent was removed under reduced pressure (Genevac HT-4), and the crude residue was purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water gradient and trifluoroacetic acid as the modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) to provide the title compound (1.9 mg, 32.7 mg theoretical, 5.8%). LC-MS m/z 400.1 (M+1).

Example 222

(Z)—N-((1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)methyl)pyrazine-2-carboxamide was prepared as follows.

A 2-dram round-bottomed vial was charged with (Z)-5-((2-(4-(aminomethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione, prepared using the general displacement procedure followed by the general TFA de-protection procedure, (56 mg, 0.175 mmol), DCM (3 mL), pyrazine-2-carbonyl chloride (25 mg, 0.175 mmol, 1 equiv.), and pyridine (0.120 mL, 1.47 mmol, 8.4 equiv.). The reaction mixture was shaken at RT for 16 h, the solvent was removed under reduced pressure (Genevac HT-4), and the crude residue was purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water gradient and trifluoroacetic acid as the modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) to provide the title compound (4.9 mg, 74.5 mg theoretical, 6.6%). LC-MS m/z 426.5 (M+1).

Example 223

(Z)—N-((1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)methyl)-2,2,2-trifluoroacetamide was prepared as follows.

A 2-dram round-bottomed vial was charged with (Z)-5-((2-(4-(aminomethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione, prepared using the general displacement procedure followed by the general TFA de-protection procedure, (56 mg, 0.175 mmol), DCM (3 mL), 2,2,2-trifluoroacetyl chloride (23 mg, 0.175 mmol, 1 equiv.), and pyridine (0.120 mL, 1.47 mmol, 8.4 equiv.). The reaction mixture was shaken at RT for 16 h, the solvent was removed under reduced pressure (Genevac HT-4), and the crude residue was purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water gradient and trifluoroacetic acid as the modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) to provide the title compound (6.5 mg, 72.7 mg theoretical, 8.9%). LC-MS m/z 416.1 (M+1).

Example 224

(S,Z)-5-((2-((1-(pyrazine-2-carbonyl)piperidin-3-yl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared as follows.

A 2-dram round-bottomed vial was charged with (S,Z)-5-((2-(piperidin-3-ylamino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione, prepared using the general displacement procedure followed by the general TFA de-protection procedure, (27 mg, 0.088 mmol), DCM (2 mL), pyrazine-2-carbonyl chloride (12.5 mg, 0.088 mmol, 1 equiv.), and pyridine (0.080 mL, 0.982 mmol, 11 equiv.). The reaction mixture was shaken at RT for 16 h, the solvent was removed under reduced pressure (Genevac HT-4), and the crude residue was purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water gradient and trifluoroacetic acid as the modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) to provide the title compound (2.6 mg, 36.1 mg theoretical, 6.4%). LC-MS m/z 412.1 (M+1).

Example 225

(Z)-3-amino-3-(1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)-N-(3-(trifluoromethoxy)benzyl)propanamide was prepared as follows.

A 2-dram round-bottomed vial was charged with (Z)-3-((tert-butoxycarbonyl)amino)-3-(1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)propanoic acid, prepared using the general displacement procedure, (25 mg, 0.052 mmol), DMF (1 mL), DIPEA (34.9 μL, 0.209 mmol, 4 equiv.), and (3-(trifluoromethoxy)phenyl)methanamine (7.85 μL, 0.052 mmol, 1 equiv.). The reaction mixture was shaken for 20 minutes then HBTU (29.8 mg, 0.079 mmol, 1.5 equiv.) was added and the reaction mixture was shaken at RT for 3 h. The solvent was removed under reduced pressure (Genevac HT-4) and the resulting solid was washed with water (2×1 mL) and dried under high vacuum to provide 20 mg of (Z)-tert-butyl (1-(1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)-3-oxo-3-((3-(trifluoromethoxy)benzyl)amino)propyl)carbamate (20 mg, 34.1 mg theoretical, 58.7%).

A 2-dram round-bottomed vial was charged with (Z)-tert-butyl (1-(1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)-3-oxo-3-((3-(trifluoromethoxy)benzyl)amino)propyl)carbamate (20 mg, 0.031 mmol), DCM (0.5 mL), and TFA (0.5 mL). The reaction mixture was shaken at RT for 16 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residue was purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water gradient and trifluoroacetic acid as the modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) to provide the title compound (15.6 mg, 16.9 mg theoretical, 92%). LC-MS m/z 551.2 (M+1)

Example 226

(Z)-methyl 2-(((1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)methyl)amino)pyrimidine-4-carboxylate was prepared as follows.

Methyl 2-((piperidin-4-ylmethyl)amino)pyrimidine-4-carboxylate was prepared as follows: A 40 mL round-bottomed vial was charged with tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (1.76 mmol, 1.1 equiv.), acetonitrile (4 mL), DiPEA (2.37 mmol, 1.5 equiv.), methyl 2,6-dichloropyrimidine-4-carboxylate (1.58 mmol, 1 equiv.), and then shaken at 85° C. for 72 h. The reaction mixture was concentrated under reduced pressure and purified on SiO₂ using a Biotage and a 10-50% EtOAc/hexanes gradient to provide the desired protected amine (233 mg, 552 mg theoretical, 42%). Methyl 2-((piperidin-4-ylmethyl)amino)pyrimidine-4-carboxylate was prepared using the general TFA de-protection procedure and used directly in the general displacement procedure to provide the title compound (4 mg, 73.4 mg theoretical, 5%). LC-MS m/z 456.1 (M+1).

Example 227

(Z)-5-((2-(4-((imidazo[1,2-b]pyridazin-6-ylamino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using a procedure similar to the procedure used in the synthesis of Example 226 to provide the title compound (12.2 mg, 45.9 mg theoretical, 26.6%). LC-MS m/z 437.5 (M+1).

Example 228

(Z)-5-((2-(4-(((1H-benzo[d]imidazol-2-yl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using a procedure similar to the procedure used in the synthesis of Example 226 to provide the title compound (21.4 mg, 45.8 mg theoretical, 46.7%). LC-MS m/z 436.5 (M+1).

Example 229

(Z)-5-((2-(4-(((7H-purin-6-yl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using a procedure similar to the procedure used in the synthesis of Example 226 to provide the title compound (12.7 mg, 41.6 mg theoretical, 30.6%). LC-MS m/z 438.5 (M+1).

Example 230

General Procedure for the Preparation of Sulfonamides

A 2-dram round-bottomed vial was charged with the appropriate sulfonyl chloride (0.072 mmol, 1 equiv.) in 0.5 mL of DMF, and then treated carefully with a solution of the appropriate amine intermediate, prepared using the general displacement procedure followed by the general TFA de-protection procedure, (0.072 mmol, 1 equiv.), DIPEA (0.288 mmol, 4 equiv.), and 1 mL of DMF. The reaction mixture was then shaken at room temperature overnight. The reaction mixture was partitioned between 2 mL DCE and 1 mL sat. NaHCO₃ and the aqueous layer was extracted with DCE (2×2 mL). The combined organic layer was the concentrated under reduced pressure (Genevac HT-4) and the crude residue was purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as the modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) to afford the sulfonamide analogs.

Example 231

(Z)—N-((1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)methyl)naphthalene-2-sulfonamide was prepared using a procedure similar to the general procedure described in Example 230 to provide the title compound (7.7 mg, 36.7 mg theoretical, 21%). LC-MS m/z 510.5 (M+1).

Example 232

(Z)—N-((1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)methyl)-6-methoxynaphthalene-2-sulfonamide was prepared using a procedure similar to the general procedure described in Example 230 to provide the title compound (15.2 mg, 38.9 mg theoretical, 39.1%). LC-MS m/z 540.5 (M+1).

Example 233

(Z)-5-chloro-N-((1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)methyl)naphthalene-2-sulfonamide was prepared using a procedure similar to the general procedure described in Example 230 to provide the title compound (9.2 mg, 39.2 mg theoretical, 23.5%). LC-MS m/z 545 (M+1).

Example 234

(Z)—N-((1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)methyl)-1-methyl-1H-indole-5-sulfonamide was prepared using a procedure similar to the general procedure described in Example 230 to provide the title compound (13.2 mg, 36.9 mg theoretical, 35.8%). LC-MS m/z 513.5 (M+1).

Example 235

Protocols for Kinase Activity Screening for CK1γ1(h), CK1γ2(h), CK1γ3(h), CK1δ(h) and CK1(y):

Kinase screening was performed by Millipore UK Ltd. Kinase dilution buffer composition: 20 mM MOPS, 1 mM EDTA, 0.01% Brij-35, 5% Glycerol, 0.1% b-mercaptoethanol, 1 mg/mL BSA.

TABLE 4 Kinase assay ATP concentration within 15 μM of K_(M). Kinase K_(M) (μM) CK1γ1 (h) 15 CK1γ2 (h) 10 CK1γ3 (h) 10 CK1δ (h) 70 CK1 (y) 45

In a final reaction volume of 25 μL, the compound of interest (at the desired concentration) and the appropriate kinase (5-10 mU) were incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 200 μM KRRRALS(p)VASLPGL (SEQ ID NO:1), 10 mM magnesium acetate and [γ-³³P-ATP] (specific activity approx. 500 cpm/pmol, concentration as required). The reaction was initiated by the addition of the MgATP mix. After incubation for 40 minutes at room temperature, the reaction was stopped by the addition of 5 μL of a 3% phosphoric acid solution. 10 μL of the reaction mixture was then spotted onto a P30 filtermat; and washed three times for 5 minutes in 75 mM phosphoric acid, and once in methanol prior to drying and scintillation counting. The estimated IC₅₀ values for several compounds are provided in Table 5.

TABLE 5 Estimated IC₅₀ values Compound Kinase IC₅₀ (nM) 4981 CK1γ1(h) 121 4981 CK1γ2(h) 19 4981 CK1γ3(h) 401 4981 CK1δ(h) >10,000 4981 CK1(y) >10,000 4993 CK1γ1(h) 5,034 4993 CK1γ2(h) 716 4993 CK1γ3(h) 3,168 4993 CK1δ(h) >10,000 4993 CK1(y) 9,853 4991 CK1γ1(h) 571 4991 CK1γ2(h) 146 4991 CK1γ3(h) 1,085 4991 CK1δ(h) >10,000 4991 CK1(y) 1,161 4999 CK1γ1(h) 163 4999 CK1γ2(h) 37 4999 CK1γ3(h) 470 4999 CK1δ(h) 3,446 4999 CK1(y) 2,990 4985 CK1γ1(h) 2,568 4985 CK1γ2(h) 191 4985 CK1γ3(h) 4,714 4985 CK1δ(h) >10,000 4985 CK1(y) 3,717 4992 CK1γ1(h) 4,543 4992 CK1γ2(h) 745 4992 CK1γ3(h) 1,736 4992 CK1δ(h) >10,000 4992 CK1(y) 1,760 4996 CK1γ1(h) 624 4996 CK1γ2(h) 27 4996 CK1γ3(h) >10,000 4996 CK1δ(h) >10,000 4996 CK1(y) 2,447 5000 CK1γ1(h) 4,036 5000 CK1γ2(h) 2,367 5000 CK1γ3(h) 3,498 5000 CK1δ(h) 9,153 5000 CK1(y) 1,719

The relative activity of the kinase as a function of the concentration of the compounds are depicted in FIGS. 1-40.

Additional IC₅₀s for CK1 are shown in Table 6:

TABLE 6 CK1 IC₅₀ values (nM) ID CK1γ1 CK1γ2 IC₅₀ CK1γ3 10189 645 10190 519 10196 63 10197 12 10202 529 102 700 10204 110 10205 127 38 131 10206 1254 77 566 10216 48

Additional % activity data is shown in Table 7.

TABLE 7 % Activity for various compounds ID CK1γ1 CK1γ2 CK1γ3 10190 80 33 94 10204 14 7 31 10191 85 72 85 10205 15 2 8 10192 108 104 96 10206 43 13 37 10193 97 94 93 10209 104 79 96 10194 92 79 78 10211 91 84 79 10196 57 15 31 10212 99 99 99 10183 86 85 74 10197 14 −2 30 10214 98 100 95 10200 82 59 77 10215 107 101 96 10202 38 15 38 10216 18 1 31 10189 64 44 67 10203 78 71 80 10217 104 93 90

Example 236

PIM kinase assays were performed by Millipore UK Ltd. IC₅₀ data is summarized in Table 8, and percent activity data is summarized in Table 9.

TABLE 8 PIM kinase IC₅₀ values ID Pim1 IC₅₀ (nM) Pim2 IC₅₀ (nM) Pim3 IC₅₀ (nM) 4981 6348 1371 4991 1775 555 4980 5320 665 4982 287 256 4983 4328 3080 4989 4492 2051 4992 784 392 4993 189 91 191 4994 1578 786 4995 1819 2297 4998 4107 2741 5000 143 155 187 5117 3400 8996 10183 1332 730 10212 304 477 10214 10216 499 163 10209 574 350 10202 857 108 10189 2966 690 10200 3226 714 10190 3978 715 10191 2110 1310 10192 1655 2438 10193 2739 3846 10194 4399 2072 10206 3124 2217 10257 51 20 13 10256 45 47 27

TABLE 9 PIM kinase percent activity at varying concentrations % activity % activity % activity 10 microM 1 microM 10 microM PIM PIM PIM PIM PIM ID PIM 1 2 PIM 1 2 3 PIM 1 2 3 4848 37 34 4980 19 6 4982 2 8 4983 26 24 4985 30 23 4987 38 11 4989 23 19 4992 4 11 4993 0 9 4994 3 5 4995 14 20 4996 10 27 4997 18 11 4998 22 16 4999 27 10 5000 19 4 5001 17 16 5113 86 54 5117 10 22 5121 105 61 5126 39 15 5132 86 61 5114 113 87 5118 92 50 5122 94 69 5127 61 67 5133 50 35 5115 77 63 5119 97 79 5124 88 59 5128 108 64 5116 106 86 5120 95 62 5125 83 49 5131 117 83 5336 103 90 5337 104 82 5338 117 103 5339 75 70 5340 98 78 5345 113 85 5349 101 94 5353 109 101 5358 89 81 5341 107 109 5346 89 97 5350 76 97 5354 87 91 5343 76 80 5347 87 105 5351 93 96 5355 50 52 5344 95 103 5348 83 92 5352 99 103 5357 100 101 5359 94 99 5376 94 108 5382 80 101 5363 86 84 5378 88 92 5369 84 122 5379 81 107 5371 102 110 5380 93 114 10178 84 122 5134 51 44 10179 63 81 10180 49 69 10181 74 93 10182 59 44 10183 8 7 10184 90 115 10185 24 20 10227 88 10244 134 10247 121 10248 121 10249 122 10211 44 41 10212 5 6 10214 51 44 10215 19 24 10216 8 21 10217 100 102 10209 11 8 10202 10 1 10189 14 4 10200 15 6 10190 16 9 10191 22 13 10192 23 25 10193 20 24 10194 23 18 10196 65 80 10197 39 38 10203 35 52 10204 35 23 10205 50 23 10206 18 17 10257 8 8 2 18 12 3 10256 9 12 0 24 28 8 10265 8 21 31 33 57 57 10264 20 30 17 49 49 46 10262 23 33 17 51 62 40 10255 34 29 36 59 52 59 10259 57 72 48 80 97 67 10258 46 44 32 82 76 56 10251 67 38 51 84 64 66 10253 67 63 54 87 81 79 10250 53 28 27 90 63 83 10263 78 82 92 91 91 85 10260 50 63 33 94 79 60 10252 65 54 38 96 83 70 10254 72 68 37 96 88 73 10261 82 99 62 100 117 87

Additional percent activity data at 10 micromolar (μM) for compounds 4981 and 4991 is depicted in Tables 10 and 11.

TABLE 10 % Activity at 10 μM. ID GSK3β(h) Pim-1(h) Pim-2(h) Pim-3(h) VRK2(h) 4981 93 50 29 57 103 4991 66 20 15 73 103

TABLE 11 PI3 Kinase 4981 4991 PI3 (p110β/p85α)(h) 99 88 PI3 (p120γ)(h) 85 61 PI3 (p110δ/p85α)(h) 86 45 PI3 (p110α/p85α)(m) 83 46 PI3 (p110β/p65α)(m) 84 46 PI3 (p110α(E545K)/p85α)(m) 75 51 PI3 (p110α(H1047R)/p85α)(m) 76 22 PI3 (p110β/p85β)(m) 99 86 PI3 (p110β/p85α)(m) 95 85 PI3 (p110δ/p85α)(m) 85 57 PI3 (p110α(E542K))/p85α)(h) 82 52 PI3 KC2 α(h) 90 84

Example 237 Cell Proliferation Studies

Inhibition of PC-3 Cells:

Cells: PC-3 cells, ATCC Passage unknown, Mycoplasma free.

Medium: DMEM Medium (GIBCO Cat#11995073) supplemented with 10% fetal bovine serum (Hyclone Cat#SH30396.03).

Seeding: 3,000 cells/well (100 μL) into 96-well plates, incubated overnight at 37° C. in a humidified 5% CO₂ atmosphere.

Treatment: Test compounds were first diluted 333-fold in the medium. Fifty microliters (50 μL) of diluted compounds were added into each well (i.e., another 3-fold dilution). The final concentration of test compounds was 10 μM. The final concentrations of the positive control (Gemcitabine, also 50 μL added in each well) is shown in FIG. 41. The cells were incubated for 72 hours after addition of the test compounds. MTS: Added 20 μL of MTS solution (Promega Cat #G5430) into each well and incubated for 4 hours. Calculation: % of inhibition+(AVE zero ctrl−AVE compound)/AVE zero ctrl*100. Results are shown in Table 12:

TABLE 12 Compound Color Inhibition ID Test No. OD value control Real OD Avg. Rate % 4981 1 2.004 2.010 1.893 0.676 1.329 1.334 1.218 1.294 0.8 4985 2 1.876 1.934 1.891 0.595 1.280 1.339 1.296 1.305 −0.1 4991 3 1.804 1.851 1.775 0.599 1.205 1.252 1.176 1.211 7.1 4999 4 1.846 1.911 1.824 0.590 1.256 1.321 1.234 1.270 2.6 Con — 1.679 2.079 1.915 0.587 1.092 1.492 1.328 1.304 0.0  1.2 μM 1.783 1.800 1.833 0.587 1.196 1.213 1.245 1.218 6.5  3.7 μM 1.769 1.800 1.841 0.587 1.182 1.213 1.253 1.216 6.7 11.1 μM 1.558 1.625 1.670 0.587 0.971 1.038 1.083 1.031 20.9 33.3 μM 1.311 1.231 1.277 0.587 0.724 0.644 0.689 0.686 47.4  100 μM 1.145 1.163 1.186 0.587 0.558 0.576 0.598 0.577 55.7  300 μM 0.805 0.925 0.833 0.587 0.218 0.338 0.245 0.267 79.5

Example 238 Cell Proliferation Studies

Inhibition of OVCAR-3 Cells

Cells: OVCAR-3 cells, ATCC Passage 4, Mycoplasma free.

Medium: RPMI-1640 Medium (GIBCO Cat#22400121) supplemented with 10% fetal bovine serum (Hyclone Cat#SH30396.03).

Seeding: 2,000 cells/well (100 μL) into 96-well plates, incubated overnight at 37° C. in a humidified 5% CO₂ atmosphere.

Treatment: Test compounds were first diluted 333-fold in the medium. Fifty microliters (50 μL) of diluted compounds were added into each well (i.e., another 3-fold dilution). The final concentration of test compounds was 10 μM. The final concentrations of the positive control (Gemcitabine, also 50 μL added in each well) is shown in FIG. 42. The cells were incubated for 72 hours after addition of the test compounds. MTS: Added 20 μL of MTS solution (Promega Cat #G5430) into each well and incubated for 4 hours. Calculation: % of inhibition+(AVE zero ctrl−AVE compound)/AVE zero ctrl*100. Results are shown in Table 13:

TABLE 13 Compound Test Color Inhibition ID No. OD value control Real OD Avg. Rate % 4981 1 0.777 0.872 0.917 0.267 0.510 0.606 0.650 0.589 19.2 4985 2 0.895 0.937 0.902 0.280 0.615 0.657 0.622 0.631 13.3 4991 3 0.532 0.557 0.571 0.252 0.280 0.305 0.319 0.301 58.7 4999 4 0.794 0.882 0.793 0.254 0.540 0.628 0.538 0.569 22.0 CON — 1.010 0.948 1.020 0.264 0.746 0.684 0.756 0.728 0.0  1.2 μM 0.781 0.948 0.851 0.264 0.517 0.684 0.586 0.596 18.2  3.7 μM 0.784 0.770 0.876 0.264 0.520 0.506 0.612 0.546 25.0 11.1 μM 0.742 0.749 0.797 0.264 0.478 0.485 0.532 0.499 31.5 33.3 μM 0.638 0.687 0.760 0.264 0.374 0.423 0.496 0.431 40.8  100 μM 0.378 0.331 0.408 0.264 0.114 0.067 0.144 0.108 85.1  300 μM 0.335 0.385 0.356 0.264 0.071 0.121 0.092 0.095 87.0

Example 239 Cell Proliferation Studies

Inhibition of LNCaP Cells

Cells: LNCaP, ATCC Passage unknown, Mycoplasma free.

Medium: RPMI-1640 Medium (GIBCO Cat#22400121) supplemented with 10% fetal bovine serum (Hyclone Cat#SH30396.03).

Seeding: 3,000 cells/well (100 μL) into 96-well plates, incubated overnight at 37° C. in a humidified 5% CO₂ atmosphere.

Treatment: Test compounds were first diluted 333-fold in the medium. Fifty microliters (50 μL) of diluted compounds were added into each well (i.e., another 3-fold dilution). The final concentration of test compounds was 10 μM. The final concentrations of the positive control (Gemcitabine, also 50 μL added in each well) is shown in FIG. 43. The cells were incubated for 72 hours after addition of the test compounds. MTS: Added 20 μL of MTS solution (Promega Cat #G5430) into each well and incubated for 4 hours. Calculation: % of inhibition+(AVE zero ctrl−AVE compound)/AVE zero ctrl*100. Results are shown in Table 14:

TABLE 14 Compound Test Color Inhibition ID No. OD value control Real OD Average Rate % 4981 1 1.532 1.471 1.686 0.264 1.267 1.207 1.422 1.299 4.1 4985 2 1.376 1.317 1.853 0.273 1.103 1.044 1.580 1.243 8.3 4991 3 1.328 1.361 1.414 0.267 1.061 1.094 1.147 1.100 18.8 4999 4 1.455 1.602 1.584 0.283 1.173 1.319 1.301 1.264 6.7 Con — 1.714 1.505 1.647 0.267 1.446 1.237 1.37 1.355 0.0  1.2 μM 1.403 1.394 1.480 0.267 1.135 1.126 1.213 1.158 14.5  3.7 μM 0.730 0.814 0.847 0.267 0.463 0.547 0.579 0.530 60.9 11.1 μM 0.379 0.410 0.413 0.267 0.112 0.142 0.145 0.133 90.2 33.3 μM 0.363 0.375 0.353 0.267 0.096 0.107 0.086 0.097 92.9  100 μM 0.377 0.406 0.396 0.267 0.109 0.139 0.128 0.126 90.7  300 μM 0.401 0.413 0.391 0.267 0.134 0.145 0.123 0.134 90.1

Example 240 Cell Proliferation Studies

Inhibition of Jurkat Cells

Cells: Jurkat cells, ATCC Passage unknown, Mycoplasma free.

Medium: RPMI-1640 Medium (GIBCO Cat#22400121) supplemented with 10% fetal bovine serum (Hyclone Cat#SH30396.03).

Seeding: 5,000 cells/well (100 μL) into 96-well plates, incubated overnight at 37° C. in a humidified 5% CO₂ atmosphere.

Treatment: Test compounds were first diluted 333-fold in the medium. Fifty microliters (50 μL) of diluted compounds were added into each well (i.e., another 3-fold dilution). The final concentration of test compounds was 10 μM. The final concentrations of the positive control (Gemcitabine, also 50 μL added in each well) is shown in FIG. 44. The cells were incubated for 72 hours after addition of the test compounds. MTS: Added 20 μL of MTS solution (Promega Cat #G5430) into each well and incubated for 4 hours. Calculation: % of inhibition+(AVE zero ctrl−AVE compound)/AVE zero ctrl*100. Results are shown in Table 15:

TABLE 15 Compound Test Color Inhibition ID No. OD value control Real OD Average Rate % 4981 1 0.752 0.847 0.793 0.292 0.460 0.555 0.501 0.505 −2.2 4985 2 0.660 0.620 0.613 0.302 0.357 0.318 0.311 0.329 33.5 4991 3 0.557 0.480 0.469 0.288 0.269 0.192 0.181 0.214 56.8 4999 4 0.718 0.694 0.622 0.274 0.443 0.419 0.348 0.403 18.4 Con — 0.830 0.659 0.827 0.278 0.552 0.382 0.548 0.494 0.0  1.2 μM 0.659 0.674 0.725 0.278 0.381 0.396 0.447 0.408 17.4  3.7 μM 0.457 0.465 0.447 0.278 0.179 0.187 0.169 0.179 63.9 11.1 μM 0.355 0.354 0.352 0.278 0.077 0.076 0.074 0.076 84.7 33.3 μM 0.254 0.249 0.254 0.278 −0.024 −0.029 −0.023 −0.026 105.2  100 μM 0.254 0.247 0.252 0.278 −0.024 −0.031 −0.025 −0.027 105.5  300 μM 0.261 0.258 0.255 0.278 −0.017 −0.020 −0.0231 −0.020 104.1

Example 241 Cell Proliferation Studies

Inhibition of MDA-MB-468 Cells

Cells: MDA-MB-468 cells, ATCC Passage unknown, Mycoplasma free.

Medium: RPMI-1640 Medium (GIBCO Cat#22400121) supplemented with 10% fetal bovine serum (Hyclone Cat#SH30396.03).

Seeding: 2,000 cells/well (100 μL) into 96-well plates, incubated overnight at 37° C. in a humidified 5% CO₂ atmosphere.

Treatment: Test compounds were first diluted 333-fold in the medium. Fifty microliters (50 μL) of diluted compounds were added into each well (i.e., another 3-fold dilution). The final concentration of test compounds was 10 μM. The final concentrations of the positive control (Gemcitabine, also 50 μL added in each well) is shown in FIG. 45. The cells were incubated for 72 hours after addition of the test compounds. MTS: Added 20 μL of MTS solution (Promega Cat #G5430) into each well and incubated for 4 hours. Calculation: % of inhibition+(AVE zero ctrl−AVE compound)/AVE zero ctrl*100. Results are shown in Table 16:

TABLE 16 Compound Test Color Inhibition ID No. OD value control Real OD Average Rate % 4981 1 0.733 1.158 0.739 0.334 0.400 0.824 0.405 0.543 22.6 4985 2 0.845 1.107 0.893 0.280 0.565 0.828 0.613 0.669 4.7 4991 3 0.688 0.936 0.665 0.278 0.411 0.659 0.388 0.486 30.8 4999 4 0.800 1.145 0.849 0.271 0.529 0.874 0.578 0.660 5.9 CON — 0.996 0.990 0.937 0.273 0.723 0.717 0.663 0.702 0.0  1.2 μM 0.871 0.867 0.840 0.273 0.598 0.594 0.567 0.586 16.4  3.7 μM 0.735 0.765 0.765 0.273 0.463 0.492 0.492 0.482 31.2 11.1 μM 0.428 0.364 0.431 0.273 0.156 0.091 0.158 0.135 80.7 33.3 μM 0.332 0.324 0.336 0.273 0.060 0.051 0.0629 0.058 91.7  100 μM 0.331 0.318 0.405 0.273 0.058 0.045 0.132 0.078 88.8  300 μM 0.323 0.294 0.309 0.273 0.050 0.022 0.0359 0.036 94.9

Example 242 Cell Proliferation Studies

Inhibition of HCT116 Cells

Cells: HCT116 cells, ATCC Passage unknown, Mycoplasma free.

Medium: DMEM Medium (GIBCO Cat#11995073) supplemented with 10% fetal bovine serum (Hyclone Cat#SH30396.03).

Seeding: 750 cells/well (100 μL) into 96-well plates, incubated overnight at 37° C. in a humidified 5% CO₂ atmosphere.

Treatment: Test compounds were first diluted 333-fold in the medium. Fifty microliters (50 μL) of diluted compounds were added into each well (i.e., another 3-fold dilution). The final concentration of test compounds was 10 μM. The final concentrations of the positive control (Gemcitabine, also 50 μL added in each well) is shown in FIG. 46. The cells were incubated for 72 hours after addition of the test compounds. MTS: Added 20 μL of MTS solution (Promega Cat #G5430) into each well and incubated for 4 hours. Measurement: Absorbance at 490 nm using MD Spectramax Plus 384 spectrophotometer. Calculation: % of inhibition+(AVE zero ctrl−AVE compound)/AVE zero ctrl*100. Results are shown in Table 17:

TABLE 17 Compound Test Color Inhibition ID No. OD value control Real OD Average Rate % 4981 1 1.906 1.900 1.911 0.356 1.550 1.544 1.555 1.550 8.9 4985 2 1.922 2.285 1.880 0.380 1.542 1.905 1.501 1.649 3.1 4991 3 1.750 1.645 1.744 0.352 1.399 1.293 1.392 1.361 20.0 4999 4 1.864 1.979 1.997 0.357 1.506 1.621 1.640 1.589 6.6 CON control 2.034 1.970 2.160 0.353 1.681 1.617 1.807 1.702 0.0  1.2 μM 1.171 1.242 1.192 0.353 0.819 0.889 0.839 0.849 50.1  3.7 μM 0.707 0.640 0.768 0.353 0.355 0.287 0.415 0.352 79.3 11.1 μM 0.573 0.565 0.653 0.353 0.220 0.213 0.300 0.244 85.6 33.3 μM 0.591 0.575 0.626 0.353 0.238 0.222 0.274 0.245 85.6  100 μM 0.541 0.606 0.655 0.353 0.188 0.254 0.303 0.248 85.4  300 μM 0.546 0.563 0.584 0.353 0.194 0.211 0.231 0.212 87.6

Example 243 Cell Proliferation Studies

Inhibition of A549 Cells

Cells: A549 cells, ATCC Passage unknown, Mycoplasma free.

Medium: DMEM Medium (GIBCO Cat#11995073) supplemented with 10% fetal bovine serum (Hyclone Cat#SH30396.03).

Seeding: 750 cells/well (100 μL) into 96-well plates, incubated overnight at 37° C. in a humidified 5% CO₂ atmosphere.

Treatment: Test compounds were first diluted 333-fold in the medium. Fifty microliters (50 μL) of diluted compounds were added into each well (i.e., another 3-fold dilution). The final concentration of test compounds was 10 μM. The final concentrations of the positive control (Gemcitabine, also 50 μL added in each well) is shown in FIG. 47. The cells were incubated for 72 hours after addition of the test compounds. MTS: Added 20 μL of MTS solution (Promega Cat #G5430) into each well and incubated for 4 hours. Measurement: Absorbance at 490 nm using MD Spectramax Plus 384 spectrophotometer. Calculation: % of inhibition+(AVE zero ctrl−AVE compound)/AVE zero ctrl*100. Results are shown in Table 18:

TABLE 18 Compound Test Color Inhibition ID No. OD value control Real OD Average Rate % 4981 1 1.610 1.820 1.696 0.358 1.253 1.462 1.338 1.351 2.9 4985 2 1.756 1.753 1.799 0.401 1.356 1.352 1.398 1.368 1.7 4991 3 1.632 1.602 1.611 0.306 1.326 1.295 1.305 1.309 6.0 4999 4 1.797 1.738 1.789 0.387 1.410 1.351 1.402 1.388 0.3 CON control 1.848 1.806 1.585 0.354 1.494 1.451 1.231 1.392 0.0  1.2 μM 1.197 1.282 1.158 0.354 0.843 0.928 0.804 0.858 38.3  3.7 μM 0.840 0.864 0.854 0.354 0.485 0.510 0.500 0.498 64.2 11.1 μM 0.733 0.750 0.762 0.354 0.378 0.396 0.407 0.394 71.7 33.3 μM 0.745 0.703 0.746 0.354 0.390 0.348 0.391 0.377 72.9  100 μM 0.651 0.643 0.671 0.354 0.297 0.289 0.317 0.301 78.4  300 μM 0.629 0.593 0.652 0.354 0.275 0.238 0.298 0.270 80.6

Example 244 Cell Proliferation Studies

Inhibition of DU145 Cells

Cells: DU145 cells, ATCC Passage unknown, Mycoplasma free.

Medium: DMEM Medium (GIBCO Cat#11995073) supplemented with 10% fetal bovine serum (Hyclone Cat#SH30396.03).

Seeding: 750 cells/well (100 μL) into 96-well plates, incubated overnight at 37° C. in a humidified 5% CO₂ atmosphere.

Treatment: Test compounds were first diluted 333-fold in the medium. Fifty microliters (50 μL) of diluted compounds were added into each well (i.e., another 3-fold dilution). The final concentration of test compounds was 10 μM. The final concentrations of the positive control (Gemcitabine, also 50 μL) added in each well) is shown in FIG. 48. The cells were incubated for 72 hours after addition of the test compounds. MTS: Added 20 μL of MTS solution (Promega Cat #G5430) into each well and incubated for 4 hours. Measurement: Absorbance at 490 nm using MD Spectramax Plus 384 spectrophotometer. Calculation: % of inhibition+(AVE zero ctrl−AVE compound)/AVE zero ctrl*100. Results are shown in Table 19:

TABLE 19 Compound Test Color Inhibition ID No. OD value control Real OD Average Rate % 4981 1 1.360 1.205 1.427 0.259 1.100 0.946 1.168 1.071 8.4 4985 2 1.522 1.724 1.551 0.411 1.112 1.314 1.140 1.188 −1.6 4991 3 1.487 1.516 1.512 0.367 1.120 1.149 1.145 1.138 2.7 4999 4 1.592 1.591 1.538 0.290 1.302 1.302 1.248 1.284 −9.8 CON control 1.470 1.566 1.469 0.332 1.138 1.234 1.137 1.170 0.0  1.2 μM 0.858 0.947 0.930 0.332 0.526 0.615 0.598 0.580 50.4  3.7 μM 0.424 0.448 0.428 0.332 0.093 0.116 0.097 0.102 91.3 11.1 μM 0.418 0.412 0.447 0.332 0.087 0.081 0.115 0.094 91.9 33.3 μM 0.404 0.425 0.457 0.332 0.072 0.093 0.125 0.097 91.7  100 μM 0.453 0.426 0.355 0.332 0.121 0.094 0.023 0.079 93.2  300 μM 0.410 0.395 0.400 0.332 0.079 0.063 0.068 0.070 94.0

Example 245 Cell Proliferation Studies

Inhibition of HCC1954 Cells

Cells: DU145 cells, ATCC Passage unknown, Mycoplasma free.

Medium: RPMI-1640 Medium (GIBCO Cat#22400121) supplemented with 10% fetal bovine serum (Hyclone Cat#SH30396.03).

Seeding: 2,000 cells/well (100 μL) into 96-well plates, incubated overnight at 37° C. in a humidified 5% CO₂ atmosphere.

Treatment: Test compounds were first diluted 333-fold in the medium. Fifty microliters (50 μL) of diluted compounds were added into each well (i.e., another 3-fold dilution). The final concentration of test compounds was 10 μM. The final concentrations of the positive control (Sorafenib, also 50 μL added in each well) is shown in FIG. 49. The cells were incubated for 72 hours after addition of the test compounds. MTS: Added 20 μL of MTS solution (Promega Cat #G5430) into each well and incubated for 4 hours. Measurement: Absorbance at 490 nm using MD Spectramax Plus 384 spectrophotometer. Calculation: % of inhibition+(AVE zero ctrl−AVE compound)/AVE zero ctrl*100. Results are shown in Table 20:

TABLE 20 Compound Test Color Inhibition ID No. OD value control Real OD Average Rate % 4981 1 1.595 1.746 1.796 0.286 1.309 1.461 1.510 1.427 2.2 4985 2 1.767 1.793 2.086 0.237 1.530 1.556 1.848 1.645 −12.8 4991 3 1.702 1.771 1.804 0.239 1.462 1.531 1.565 1.519 −4.2 4999 4 1.617 1.823 1.816 0.227 1.389 1.596 1.589 1.525 −4.6 Con control 1.470 1.861 1.772 0.243 1.227 1.618 1.529 1.458 0.0  1.2 μM 1.750 1.557 1.710 0.243 1.507 1.314 1.467 1.429 2.0  3.7 μM 1.694 1.560 1.554 0.243 1.451 1.317 1.311 1.360 6.8 11.1 μM 1.479 1.601 1.482 0.243 1.236 1.358 1.238 1.278 12.4 33.3 μM 0.296 0.265 0.275 0.243 0.053 0.022 0.032 0.036 97.5  100 μM 0.324 0.309 0.313 0.243 0.081 0.066 0.070 0.072 95.0  300 μM 0.526 0.522 0.539 0.243 0.283 0.279 0.296 0.286 80.4

Example 246 Cell Proliferation Studies

Inhibition of Caco-2 Cells

Cells: Caco-2 cells, ATCC Passage 109, Mycoplasma free.

Medium: DMEM Medium (GIBCO Cat#11995073) supplemented with 10% fetal bovine serum (Hyclone Cat#SH30396.03).

Seeding: 3,000 cells/well (100 μL) into 96-well plates, incubated overnight at 37° C. in a humidified 5% CO₂ atmosphere.

Treatment: Test compounds were first diluted 333-fold in the medium. Fifty microliters (50 μL) of diluted compounds were added into each well (i.e., another 3-fold dilution). The final concentration of test compounds was 10 μM. The final concentrations of the positive control (Sorafenib, also 50 μL added in each well) is shown in FIG. 50. The cells were incubated for 72 hours after addition of the test compounds. MTS: Added 20 μL of MTS solution (Promega Cat #G5430) into each well and incubated for 4 hours. Measurement: Absorbance at 490 nm using MD Spectramax Plus 384 spectrophotometer. Calculation: % of inhibition+(AVE zero ctrl−AVE compound)/AVE zero ctrl*100. Results are shown in Table 21:

TABLE 21 Compound Test Color Inhibition ID No. OD value control Real OD Average Rate % 4981 1 1.392 1.571 1.473 0.391 1.001 1.180 1.082 1.088 3.8 4985 2 1.535 1.572 1.512 0.351 1.184 1.221 1.160 1.188 −5.1 4991 3 1.319 1.287 1.344 0.367 0.952 0.920 0.977 0.949 16.0 4999 4 1.393 1.485 1.432 0.342 1.051 1.143 1.090 1.094 3.2 Con control 1.415 1.516 1.499 0.346 1.068 1.169 1.153 1.130 0.0  1.2 μM 1.528 1.497 1.430 0.346 1.182 1.151 1.083 1.139 −0.7  3.7 μM 1.471 1.408 1.436 0.346 1.124 1.062 1.089 1.092 3.4 11.1 μM 1.090 1.098 1.139 0.346 0.743 0.752 0.792 0.763 32.5 33.3 μM 0.393 0.383 0.366 0.346 0.047 0.037 0.020 0.034 96.9  100 μM 0.418 0.396 0.392 0.346 0.072 0.050 0.045 0.056 95.1  300 μM 0.579 0.600 0.638 0.346 0.233 0.253 0.292 0.259 77.1

Example 247

IC₅₀ determination of compound 4991 against three cancer cell lines

Additional cell inhibition studies were performed by Crown Biosciences. The materials are described in Table 22.

TABLE 22 Human Positive Incubation cancer Cell line Medium drug time Ovary OVCAR-3 RPMI 1640 + 10% FBS Cisplatin 72 h cancer OVCAR-8 RPMI 1640 + 10% FBS 72 h SK-OV-3 McCoy's 5a + 10% FBS 72 h

The dose response curves of compound 4991 compared to cisplatin, as well as the calculated IC₅₀ values, are shown in FIGS. 51-53.

Example 248

In vitro ADME assays of PAMPA and human and rat hepatic microsomal stability.

The generic gradient HPLC and MS method summarized in Table 22 was used for the analysis of compounds 4981, 4985, 4991 and 4999.

TABLE 23 HPLC conditions. Instrument Applied Biosystems API 4000 mass spectrometer Ionization Mode Electrospray, positive ions MRM 4981: 382.2 → 178.1 4985: 369.1 → 178.1 4991: 370.1 → 178.1 4999: 368.2 → 178.1 Column ACE 2 C18, 2.1 × 50 mm, 3 μm Eluent A 2 mM ammonium acetate, 0.1% formic acid in 95:5 water:methanol Eluent B 2 mM ammonium acetate, 0.1% formic acid in 95:5 methanol:water Pump Gradient Program Time (min) % A % B 0 75 25 0.5 75 25 1.00 0 100 2.00 0 100 2.10 75 25 2.50 75 25 Flow (mL/min) 0.5 Column Temperature Ambient Injection Volume 3-30 Sample Temperature Ambient Run Time (min) 2.5

Parallel artificial membrane permeability assays (PAMPA) were performed with the compounds 4981, 4985, 4991 and 4999. The target concentration in the assay was 10 μM, prepared by diluting (1000-fold) the 10 mM stock solutions in DMSO into PBS, pH 7.4. The final DMSO concentration was 0.1%. The 10 μM solutions were added, 300 μL, to wells in the donor plate. The receiver plate, which contained 200 μL of PBS, pH 7.4 per well, was placed in the donor plate and the assembly was incubated for 5 hours at ambient temperature. At the end of the incubation period the plates were separated and the compound concentrations in each solution were determined by LC/MS/MS. The assay was performed in triplicate. Dexamethasone and verapamil were used as reference compounds. The permeability, P_(e), and mass retention, R, of each compound were calculated using the following equations, and the results are summarized in Table 17. The results for dexamethasone and verapamil were consistent with historical data.

$P_{e} = \frac{{- {\ln\left\lbrack {1 - {C_{A{(t)}}/C_{E}}} \right\rbrack}} \times 10^{7}}{A \times \left( {{1/V_{D}} + {1/V_{A}}} \right) \times t}$ $R = {1 - \frac{{C_{D{(t)}}V_{D}} + {C_{A{(t)}}V_{A}}}{C_{0}V_{D}}}$ Where: C₀ is the initial concentration in the donor well (μM) C_(D(t)) is the concentration in the donor well after incubation (μM) C_(A(t)) is the concentration in the acceptor well after incubation (μM) V_(D) is the volume in the donor well (0.3 mL) V_(A) is the volume in the acceptor well (0.2 mL) C_(E) is (C_(D(t))V_(D)+C_(A(t))V_(A))/(V_(D)+V_(A)) A is the filter area (0.3 cm2) t is the incubation time (18,000 s).

TABLE 24 PAMPA Assay data summary. Compound Permeability P_(e) (nm/s) Mass Retention R (%) 4981 6.0 0 4985 125 20 4991 99 0 4999 48 35 Verapamil 75 20 Dexamethasone 9.0 9

Hepatic microsomal assays were performed with 4981, 4985, 4991 and 4999 in human and rat (Sprague-Dawley). Protein concentrations of 0.4 (human) and 0.2 mg/mL (rat) with an NADPH regenerating cofactor system (2.6 mM NADP+, 6.6 mM glucose-6-phosphate, 0.8 U/mL glucose-6-phosphate dehydrogenase, and 6.6 mM magnesium chloride) were used. A 100 μM 20% DMSO/80% acetonitrile working stock of each of the compounds was diluted 100 fold resulting in 1 μM compound/1% final organic reaction concentrations. Time points were removed at 0 and 60 minutes. At each time point, 100 μL of the incubation suspension was added to 200 μL of acetonitrile containing internal standard (tolbutamide), followed by centrifugation at 3,220 rcf for 10 minutes. Two hundred (200) μL of the resulting supernatants were removed, dried under nitrogen and reconstituted in 100 μL of 2 mM ammonium acetate, 0.1% formic acid in 50% methanol prior to analysis by LC/MS/MS. Testosterone and dexamethasone were used as reference compounds. Table 25 summarizes the results. The results for testosterone and dexamethasone were consistent with historical data.

TABLE 25 Hepatic microsomal stability summary % remaining after incubation Compound Rat Microsomes Human Microsomes 4981 14 63 4985 0.4 46 4991 0.6 55 4999 0.4 3.6 Testosterone 0.6 42 Dexamethasone 91 85

Materials used are summarized in Table 26.

TABLE 26 Materials. Material Supplier Part No. Lot No. Testosterone Sigma T1500 087K1440 Dexamethasone Sigma D1756 096K1805 Verapamil Aldrich 381195 12731MA Tolbutamide Sigma T0891 076K1277 PBS Sigma P3813 096K8204 Ammonium acetate J. T. Baker 0599-08 E49H15 Formic acid Acros Organics 147930250   AO266198 Acetonitrile EMD AX0145-1 49099 DMSO Alfa Aeser  32434 D04R008 Isopropanol J. T. Baker 9827-03 C38H23 Methanol EMD MX0486-1 49178 0.5M Potassium BD Gentest 451201 06123 Phosphate pH 7.4 PAMPA plate BD Gentest 353015 431256  Human microsomes BD Gentest 452161 18888 Rat microsomes BD Gentest 452501 21027 NADPH Regeneration BD Gentest 451220 51893 System Solution A NADPH Regeneration BD Gentest 451220 47758 System Solution B water House DI (Barnstead Nanopure) LC/MS equipment: Chromatograph: Shimadzu LC-20 AD Autosampler: CTC HTS PAL MS: API 4000 Software System Analyst Software, Version 1.4.2.

Example 249 Selected Cell Proliferation Inhibition Data

Cell Lines:

Human Positive Incubation cancer Cell line Medium drug time Multiple MV4-11 IMDM Cisplatin 72 hours Myeloma RPMI-8226 RPMI-1640 NCI-H929 RPMI-1640 + 0.05 mM 2- mercaptoethanol

All cells were cultured in media supplemented with 10% FBS except for which are marked specially, in the temperature of 37° C., 5% CO₂ and 95% humidity. All culture media were purchased from GIBCO (USA, IMDM Cat. 12200-036; RPMI Medium 1640 Cat. 31800-022; 2-mercaptoethanol Cat. 21985-023).

Reagents:

CellTiter 96® AQueous MTS reagent powder (Cat. No.: G11 12, Promega. Store MTS Reagent Powder desiccated at 4° C. protected from light.)

Phenazine methosulfate (PMS) (Product No.: P9625, SIGMA. Store PMS Powder desiccated at 4° C. protected from light.)

Preparation of PMS Solution:

0.92 mg/mL PMS in DPBS Filter-sterilize through a 0.2 m filter into a sterile, light-protected container. Store at −20° C.

Preparation of MTS Solution:

The following protocol is recommended for the preparation of 21 mL of MTS solution (sufficient for ten 96-well plates).

-   a. Select a light-protected container or wrap a container with foil. -   b. Add 21 mL of DPBS to the container. -   c. Weigh out 42 mg of MTS Reagent Powder and add to DPBS. -   d. Mix at moderate speed on a magnetic stir plate for 15 minutes or     until the MTS is completely dissolved. -   e. Measure the pH of the MTS solution. The optimum pH is between pH     6.0 to 6.5. If the solution is above pH 6.5, adjust to pH 6.5 with     1N HC1. -   f. Filter-sterilize the MTS solution through a 0.2 μm filter into a     sterile, light protected container. -   g. Store the MTS solution at −20° C., protected from light.     Preparation of the Mixture of MTS/PMS: -   a. In order to prepare reagents sufficient for one 96-well plate     containing cells cultured in a 100 μL volume, thaw the MTS solution     and the PMS solution. It should take approximately 90 minutes at     room temperature or 10 minutes in a 37° C. water bath to completely     thaw the 20 mL size of MTS solution. (Note: For convenience, the     first time the product is thawed, the entire contents of the 1 mL     tube of PMS solution can be transferred to the 20 mL bottle of MTS     solution. This mixture should be stored at −20° C. between uses. If     storing PMS and MTS solutions at 4° C., do not combine these     solutions until immediately before addition to the assay plate.) -   b. Remove 2.0 mL of MTS solution from the amber reagent bottle using     aseptic technique and transfer to a test tube. -   c. Add 100 μL of PMS solution to the 2.0 mL of MTS solution     immediately before addition to the culture plate containing cells. -   d. Gently swirl the tube to ensure complete mixing of the combined     MTS/PMS solution.     Equipment:

SpectraMAX plus microplate spectrophotometer Model 3011, Molecular Devices Corp. (California, USA); CO₂ water jacketed incubator, Therma (USA). Reverse microscope, Chongguang XDS-1B, Chongqing Guangdian Corp. (Chongqing, P. R. China).

Cytotoxicity and IC₅₀ Determination:

-   1. The cells were harvested respectively during the logarithmic     growth period and counted with hemocytometer. The cell viability was     over 98% by trypan blue exclusion. -   2. Cell concentrations were adjusted to 2.22×10⁵ or 1.11×10⁵ or     5.56×10⁴ cells/mL with respective medium. -   3. 90 μL cell suspensions were added to 96-well plates (triplicates     for each cell concentration), the final cell densities were 2×10⁴ or     1×10⁴ or 5×10³ cells/well. The density of 5×10³ cells/well was used     for the first test. The appropriate cell density was determined and     adjusted according to the results of the first test. -   4. The next day, test article or positive drugs were dissolved with     DMSO as stock solution at the concentration of 20 mM. -   5. 10 μL drug solution was dispensed in each well (triplicate for     each drug concentration). -   6. Plates were cultured for another 72 hours, then measured by means     of MTS assay. -   7. MTS/PMS solution was prepared immediately prior to use. 20 μL of     the mixture was introduced into each well of the 96-well assay plate     containing 100 μL culture medium. (The final reaction volume was 120     μL). -   8. Plate was incubated for 1-4 hours at 37° C. in a humidified 5%     CO₂ atmosphere. -   9. Absorbance at 490 nm was recorded using SpectraMAX Plus     microplate spectrophotometer.     Data Analysis:

The software of GraphPad Prism version 5 was used to calculate IC₅₀. The graphical curves were fitted using a nonlinear regression model with a sigmoidal dose.

Results

Results are shown in Tables 27 and 28.

TABLE 27 IC₅₀ values (μM) Example MV4-11 RPMI 8226 NCI-H929 155 12.49 NC 3.964 120 4.054 1.538 2.806 180 10.95 9.135 10.94 9 6.782 16.14 11.54 181 1.199 3.412 4.415 182 2.025 11.87 7.076 183 1/829 9.604 4.603 140 5.514 11.19 8.843 189 4.712 8.324 3.045 191 2.397 6.862 3.264

TABLE 28 Percent inhibition at 30 μM of Compound Example MV4-11 RPMI 8226 NCI-H929 155 97.60 53.87 73.72 120 95.09 76.43 89.78 180 90.71 79.74 100 9 91.08 71.25 91.44 181 96.63 82.15 93.5 182 91.09 90.21 96.52 183 94.36 82.34 98.62 140 94.29 65.26 96.73 189 97.91 99.87 98.51 191 87.43 93.08 93.96

Example 250

TABLE 29 Percent Activity of Enzyme When Treated with 300 nM of Compound (ATP present at Km of enzyme) Pim- Pim- Example CK1γ2(h) CK1(y) CK2(h) Pim-1(h) 2(h) 3(h) 86 26 102 83 51 105 87 80 38 40 33 56 88 91 102 52 54 102 89 100 82 99 116 110 90 81 38 22 22 62 91 79 57 36 32 102 92 103 99 33 56 47 14 93 108 88 68 54 48 30 94 19 99 98 97 101 90 96 87 90 65 73 44 57 97 83 101 70 49 22 69 98 67 89 59 40 27 39 99 85 96 79 39 6 43 99 81 97 84 47 17 43 100 108 93 45 71 64 48 101 104 97 71 42 46 20 102 101 101 84 94 91 53 103 90 97 73 114 138 99 104 89 99 82 75 72 42 105 94 96 84 101 92 81 106 67 91 47 46 22 44 107 95 97 88 72 56 47 108 79 100 90 49 18 57 109 82 82 59 68 49 57 110 58 94 62 54 31 48 111 102 104 96 71 60 51 112 98 95 82 92 88 81 113 82 87 64 64 46 40 114 77 88 56 62 36 42 115 55 94 67 50 28 55 116 83 96 61 59 45 57 117 71 91 67 37 16 53 118 98 97 68 45 56 46 119 79 100 33 25 6 48 120 72 87 43 36 43 69 121 81 115 55 74 37 82 122 64 96 71 43 50 68 123 71 99 106 92 94 109 124 92 110 91 89 62 101 125 78 97 45 49 45 69 126 74 89 86 87 81 105 127 94 104 95 77 82 86 128 52 97 86 75 84 99 129 85 87 76 99 87 100 130 96 92 64 94 85 96 131 100 102 56 72 50 71 132 80 94 34 79 64 65 133 82 86 57 98 66 101 134 31 77 57 102 88 118 135 82 99 69 59 48 82 136 36 101 71 80 49 72 137 97 112 106 100 97 97 138 81 112 74 66 46 80 139 87 55 123 42 23 88 140 52 79 26 45 53 48 142 96 103 85 84 87 143 78 79 15 14 3 3 144 103 81 5 25 10 3 145 100 106 105 104 104 85 146 93 93 87 103 82 74 147 93 76 23 33 25 8 148 98 88 42 70 40 25 149 107 108 53 74 40 49 150 97 97 77 49 29 23 151 95 78 42 38 19 23 152 98 98 64 85 58 39 153 100 88 69 89 85 54 154 98 106 77 45 30 16 155 98 88 74 7 12 5 156 83 99 54 83 68 87 157 63 89 80 53 30 13 158 53 96 96 90 94 115 159 93 95 62 49 22 27 161 101 97 71 31 46 30 162 97 101 73 86 67 76 163 94 105 108 99 90 100 164 112 98 109 97 108 90 165 102 106 97 91 88 90 166 103 104 109 18 61 61 167 108 127 91 14 44 2 168 100 99 48 47 82 171 101 103 79 96 95 89 172 105 96 81 33 36 21 173 101 104 87 90 99 106 174 81 84 75 18 21 8 175 46 82 102 51 57 61 176 86 87 67 28 34 15 177 87 86 76 22 26 12 178 91 101 75 105 89 96 179 110 105 105 96 104 95 180 66 84 80 8 15 11 181 63 72 73 17 16 8 182 56 86 61 9 10 4 183 91 60 73 5 7 3 184 84 95 81 19 28 9 185 87 91 71 23 26 6 186 86 67 72 18 22 12 187 88 95 77 40 53 16 188 85 81 71 36 41 16 189 33 38 49 1 6 3 190 60 64 73 3 16 2 191 65 64 63 4 14 4 192 52 95 80 45 37 46 193 90 89 71 26 34 12 194 72 66 75 17 24 6 195 84 92 81 36 25 11 196 99 99 93 50 55 51 197 102 106 94 43 58 54 198 104 106 98 60 44 36 199 91 98 107 99 90 99 200 92 101 101 95 92 100 201 103 110 104 93 92 106 202 84 97 85 84 72 87 203 95 103 84 25 58 51 204 91 86 74 19 40 25 205 88 72 81 24 47 17 206 103 87 21 48 26 24 207 103 77 94 18 67 20 208 99 104 39 36 17 21 209 91 106 54 42 41 42 211 54 93 106 71 24 61 212 28 96 90 75 46 53 214 41 79 77 25 13 16 215 51 86 97 34 22 41 216 39 92 60 40 10 76 217 109 116 101 91 105 218 82 80 96 91 100 219 55 100 58 57 41 50 220 98 114 102 98 91 115 221 97 90 85 92 78 78 222 37 78 67 69 25 78 223 28 100 89 56 23 79 224 53 64 71 16 15 9 225 66 91 67 61 47 55

Example 251

TABLE 30 IC₅₀ of Compound (nM) (ATP present at Km of enzyme) Pim- Pim- Example CK1γ2(h) CK1(y) CK2(h) Pim-1(h) 2(h) 3(h) 86 86 87 261 295 80 263 90 291 97 89 419 91 222 255 127 1000 92 186 628 228 31 94 38 98 422 204 136 169 99 137 18 199 106 361 166 127 298 117 164 50 436 119 176 186 16 267 120 676 >1000 214 170 225 271 143 66 20 5 3 144 23 78 18 9 147 134 258 90 31 151 415 246 98 171 155 19 14 9 159 >1000 104 231 172 157 142 46 174 58 75 16 176 669 487 108 18 177 705 96 87 22 180 13 15 15 181 79 44 34 189 164 334 364 4 9 4 191 6 23 5 204 99 217 109 205 54 199 38 208 129 288 43 65 214 95 35 60 219 476 475 146 249

INCORPORATION BY REFERENCE

All of the U.S. patents and U.S. published patent applications cited herein are hereby incorporated by reference.

EQUIVALENTS

While several embodiments of the present invention have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the functions and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the present invention. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the teachings of the present invention is/are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the scope of the present invention. 

We claim:
 1. A compound of formula 1:

or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence: W and X are independently oxygen or sulfur; Z¹, Z² and Z³ are independently C—R²⁰ or N, provided that at least one of Z¹ and Z² is N; R¹ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —COR⁶, —C(O)OR⁶, —SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —[C(R⁴)₂]_(p)—R⁵; R² and R³ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶, —SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), —P(O)(OR⁶)(OR⁷); or R² and R³ are joined together to form an optionally substituted heterocyclic ring; R⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl; R⁵ is selected from the group consisting of aryl, heteroaryl, heterocyclyl, —N(R⁸)(R⁹), —N(R⁸)COR⁹, —N(R⁸)C(O)OR⁹, —N(R⁸)SO₂(R⁹), —CON(R⁸)(R⁹), —OC(O)N(R⁸)—(R⁹), —SO₂N(R⁸)(R⁹), —OC(O)OR⁸, —COOR⁹, —C(O)N(OH)(R⁸), —OS(O)₂OR⁸, —S(O)₂OR⁸, —S(O)₂R⁸, —OR⁸, —COR⁸, —OP(O)(OR⁸)(OR⁸), —P(O)(OR⁸)(OR⁸) and —N(R⁸)P(O)(OR⁹)(OR⁹); R⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; R⁷ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R⁶ and R⁷ are joined together to form a heterocyclic ring; R⁸ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; R⁹ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R⁸ and R⁹ are joined together to form a heterocyclic ring; R²⁰ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, halo, haloalkyl, trifluoromethyl, fluoroalkyl, perfluoroalkyl, thio, cyano, hydroxy, methoxy, alkoxy, phenoxy, aryloxy, heteroaryloxy, carboxyl, alkoxycarbonyl, acyl, nitro, amino, alkylamino, arylamino, heteroarylamino, amido, acylamino, sulfate, sulfonate, sulfonyl, sulfoxido, sulfonamido, sulfamoyl, —[C(R⁴)₂]_(p)—R⁵, NR¹⁴R¹⁵, OR¹⁶, O—[C(R⁴)₂]_(p)—R⁵, NR¹⁴—[C(R⁴)₂]_(p)R⁵ and SR¹⁶; R¹⁴ and R¹⁵ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶, —SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —P(O)(OR⁶)(OR⁷); or R¹⁴ and R¹⁵ are joined together to form an optionally substituted heterocyclic ring; R¹⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, and —C(O)N(R⁶)(R⁷); and p is 1, 2, 3, 4, 5, or 6; wherein any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted.
 2. The compound of claim 1, wherein W and X are oxygen.
 3. The compound of claim 1, wherein Z¹ and Z² are nitrogen; and Z³ is C—R²⁰.
 4. The compound of claim 1, wherein R¹ is hydrogen.
 5. The compound of claim 1, wherein W and X are oxygen, Z¹ and Z² are each nitrogen, Z³ is C—R²⁰ and R¹ is hydrogen.
 6. The compound of claim 5, wherein R² and R³ are joined together to form an optionally substituted heterocyclic ring.
 7. The compound of claim 6, wherein the optionally substituted heterocyclic ring is selected from the group consisting of piperazinyl, homopiperizinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, 1,4-diazepan-5-onyl and quinolinyl.
 8. The compound of claim 5, wherein R²⁰ is hydrogen.
 9. The compound of claim 1, wherein the compound is a compound of formula 2:

or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence: R¹ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —COR⁶, —C(O)OR⁶, —SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —[C(R⁴)₂]_(p)R⁵; R² and R³ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶, —SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷)—P(O)(OR⁶)(OR⁷); or R² and R³ are joined together to form an optionally substituted heterocyclic ring; R⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl; R⁵ is selected from the group consisting of aryl, heteroaryl, heterocyclyl, —N(R⁸)(R⁹), —N(R⁸)COR⁹, —N(R⁸)C(O)OR⁹, —N(R⁸)SO₂(R⁹), —CON(R⁸)(R⁹), —OC(O)N(R⁸)—(R⁹), —SO₂N(R⁸)(R⁹), —OC(O)OR⁸, —COOR⁹, —C(O)N(OH)(R⁸), —OS(O)₂OR⁸, —S(O)₂OR⁸, —S(O)₂R⁸, —OR⁸, —COR⁸, —OP(O)(OR⁸)(OR⁹), —P(O)(OR⁸)(OR⁹) and —N(R⁸)P(O)(OR⁹)(OR⁹); R⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; R⁷ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl, or R⁶ and R⁷ are joined together to form a heterocyclic ring; R⁸ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; R⁹ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R⁸ and R⁹ are joined together to form a heterocyclic ring; R²⁰ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, halo, haloalkyl, trifluoromethyl, fluoroalkyl, perfluoroalkyl, thio, cyano, hydroxyl, methoxy, alkoxy, phenoxy, aryloxy, heteroaryloxy, carboxyl, alkoxycarbonyl, acyl, nitro, amino, alkylamino, arylamino, heteroarylamino, amido, acylamino, sulfate, sulfonate, sulfonyl, sulfoxido, sulfonamido, sulfamoyl, —[C(R⁴)₂]_(p)—R⁵; NR¹⁴R¹⁵, OR¹⁶, and SR¹⁶; R¹⁴ and R¹⁵ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, —C(O)OR⁶, —SO₂(R⁶), —C(O)N(R⁶)(R⁷), —SO₂N(R⁶)(R⁷), and —P(O)(OR⁶)(OR⁷); or R¹⁴ and R¹⁵ are joined together to form an optionally substituted heterocyclic ring; R¹⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR⁶, and —C(O)N(R⁶)(R⁷); and p is 1, 2, 3, 4, 5, or 6; wherein any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted.
 10. The compound of claim 9, wherein R¹ is hydrogen.
 11. The compound of claim 10, wherein R²⁰ is hydrogen.
 12. The compound of claim 11, wherein R² and R³ are joined together to form an optionally substituted heterocyclic ring.
 13. The compound of claim 12, wherein R² and R³ are joined together to form an optionally substituted heterocyclic ring selected from the group consisting of:

wherein, independently for each occurrence: R¹⁰ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R⁴)₂]_(p)—R⁵, —COR¹², —C(O)OR¹², —SO₂(R¹²), —C(O)N(R¹²)(R¹³), —SO₂N(R¹²)(R¹³), and —P(O)(OR¹²)(OR¹³); R¹² and R¹³ are selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R¹² and R¹³ are joined together to form a heterocyclic ring; R¹¹ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, haloalkyl, thio, cyano, hydroxyalkyl, alkoxy, alkylalkoxy, alkylthio, nitro, cyano, —N(R¹⁷)(R¹⁸), —N(R¹⁷)COR¹⁸, —N(R¹⁷)C(O)OR¹⁸, —N(R¹⁷)SO₂(R¹⁸), —CON(R¹⁷)(R¹⁸), —OC(O)N(R¹⁷)—(R¹⁸), —SO₂N(R¹⁷)(R¹⁸), —OC(O)OR¹⁷, —COOR¹⁷, —C(O)N(OH)(R¹⁷), —OS(O)₂OR¹⁷, —S(O)₂OR¹⁷, —S(O)₂R¹⁷, —OR¹⁷, —COR¹⁷, —OP(O)(OR¹⁷)(OR¹⁸), —P(O)(OR¹⁷)(OR¹⁸), —N(R¹⁷)P(O)(OR¹⁸)(OR¹⁸), and —[C(R⁴)₂]_(p)—R⁵; R¹⁷ and R¹⁸ selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R¹⁷ and R¹⁸ are joined together to form a heterocyclic ring; and n is 0, 1, 2, or 3; wherein any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted.
 14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:


15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:


16. The compound of claim 1, wherein the compound is an inhibitor of PIM1, PIM2, or PIM3.
 17. The compound of claim 16, wherein the compound has an IC₅₀ of less than 5000 nM for PIM1, PIM2 or PIM3.
 18. The compound of claim 17, wherein the compound has an IC₅₀ of less than 1000 nM for PIM1, PIM2, or PIM3.
 19. The compound of claim 18, wherein the compound has an IC₅₀ of less than 500 nM for PIM1, PIM2, or PIM3. 